Tri-substituted phenyl or pyridine derivatives

ABSTRACT

Compounds of general formula (1) are described:                    
     wherein 
     ═W— is (1) ═C(Y)— where Y is a halogen atom, or an alkyl or —XR a  group where X is —O—, —S(O) m — [where m is zero or an integer of value 1 or 2], or —N(R b )— [where R b  is a hydrogen atom or an optionally substituted alkyl group] and R a  is a hydrogen atom or an optionally substituted alkyl group or, (2) ═N—; 
     L is (1) a —C(R)═C(R 1 )(R 2 ) or [—CH(R)] n CH(R 1 )(R 2 ) group; is (2) a —(X a ) n Alk′Ar′, or Alk′X a Ar′ group; or is (3) X a R 1 ; 
     Z is a group (A), (B), (C) or (D):                    
      wherein 
     Ar is a monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms; 
     Z 1 is a group —NR 12 C(O)— [where R 12  is a hydrogen atom or an optionally substituted alkyl or (Alk) t Ar group], —C(O)NR 12 —, —NR 12 C(S)—, —C(S)NR 12 —, —C≡C—, —NR 12 SO 2 —, or —SO 2 NR 12 —; 
     Alk is an optionally substituted straight or branched alkyl chain optionally interrupted by an atom or group X; 
     t is zero or an integer of value 1, 2 or 3; 
     R 3  is a hydrogen or a fluorine atom or an optionally substituted straight or branched alkyl group or an OR 11  group [where R 11  is a hydrogen atom or an optionally substituted alkyl, alkenyl, alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamido group]; 
     R 4  is a hydrogen atom or an optionally substituted alkyl, —CO 2 R 8 , —CSNR 9 R 10 , —CN, —CH 2 CN, or —(CH 2 ) t Ar group where t is zero or an integer of value 1, 2 or 3 and Ar is a monocyclic or bicyclic aryl group optionally containing one or more heteroatoms selected from oxygen, sulphur or nitrogen atoms; provided that when L is a group of type (2) or (3) above then Z is a group of type (A) or type (B) in which R 4  is a —(CH 2 ) t Ar group; 
     R 5  is a group —(CH 2 ) t Ar; 
     R 6  is a hydrogen or a fluorine atom, or an optionally substituted alkyl or —CO 2 R 8 , —CONR 9 R 10 , —CSNR 9 R 10 , —CN or —CH 2 CN group; 
     R 7  is a hydrogen or a fluorine atom, an optionally substituted straight or branched alkyl group, or an OR c  group where R c  is a hydrogen atom or an optionally substituted alkyl or alkenyl group, alkoxyalkyl, alkanoyl, formyl, carboxamido or thiocarboxamido group; and the salts, solvates, hydrates, prodrugs and N-oxides thereof. 
     Compounds according to the invention are phosphodiesterase type IV inhibitors and are useful in the prophylaxis and treatment of disease such as asthma where unwanted inflammatory response or muscular spasm is present.

This invention relates to a novel series of tri-substituted phenylderivatives, to processes for their preparation, to pharmaceuticalcompositions containing them, and to their use in medicine.

Many hormones and neurotransmitters modulate tissue function byelevating intra-cellular levels of adenosine 3′,5′-cyclic monophosphate(cAMP). The cellular levels of cAMP are regulated by mechanisms whichcontrol synthesis and breakdown. The synthesis of cAMP is controlled byadenyl cyclase which may be directly activated by agents such asforskolin or indirectly activated by the binding of specific agonists tocell surface receptors which are coupled to adenyl cyclase. Thebreakdown of cAMP is controlled by a family of phosphodiesterase (PDE)isoenzymes, which also control the breakdown of guanosine 3′,5′-cyclicmonophosphate (cAMP). To date, seven members of the family have beendescribed (PDE I-VII) the distribution of which varies from tissue totissue. This suggests that specific inhibitors of PDE isoenzymes couldachieve differential elevation of cAMP in different tissues, [forreviews of PDE distribution, structure, function and regulation, seeBeavo & Reifsnyder (1990) TIPS, 11: 150-155 and Nicholson et al (1991)TIPS, 12: 19-27].

There is clear evidence that elevation of cAMP in inflammatoryleukocytes leads to inhibition of their activation. Furthermore,elevation of cAMP in airway smooth muscle has a spasmolytic effect. Inthese tissues, PDE IV plays a major role in the hydrolysis of cAMP. Itcan be expected, therefore, that selective inhibitors of PDE IV wouldhave therapeutic effects in inflammatory diseases such as asthma, byachieving both anti-inflammatory and bronchodilator effects.

The design of PDE IV inhibitors has met with limited success to date, inthat many of the potential PDE IV inhibitors which have been synthesisedhave lacked potency and/or have been capable of inhibiting more than onetype of PDE isoenzyme in a non-selective manner. Lack of a selectiveaction has been a particular problem given the widespread role of cAMPin vivo and what is needed are potent selective PDE IV inhibitors withan inhibitory action against PDE IV and little or no action againstother PDE isoenzymes.

We have now found a novel series of tri-substituted phenyl derivatives,members of which are potent inhibitors of PDE IV at concentrations atwhich they have little or no inhibitory action on other PDE isoenzymes.These compounds inhibit the human recombinant PDE IV enzyme and alsoelevate cAMP in isolated leukocytes. The compounds of the invention aretherefore of use in medicine, especially in the prophylaxis andtreatment of asthma.

Thus according to one aspect of the invention, we provide a compound offormula (1)

wherein

═W— is (1) ═C(Y)— where Y is a halogen atom, or an alkyl or —XR^(a)group where X is —O—, —S(O)_(m)— [where m is zero or an integer of value1 or 2], or —N(R^(b))— [where R^(b) is a hydrogen atom or an optionallysubstituted alkyl group] and R^(a) is a hydrogen atom or an optionallysubstituted alkyl group or, (2) ═N—;

L is (1) a —C(R)═C(R¹)(R²) or [—CH(R)]_(n)CH(R¹)(R²) group where R is ahydrogen or a fluorine atom or a methyl group, and R¹ and R², which maybe the same or different, is each a hydrogen or fluorine atom or anoptionally substituted alkyl, alkenyl, alkynyl, alkoxy, alkylthio,—CO₂R⁸ [where R⁸ is a hydrogen atom or an optionally substituted alkyl,aralkyl or aryl group], —CONR⁹R¹⁰ [where R⁹ and R¹⁰, which may be thesame or different are defined for R⁸], —CSNR⁹R¹⁰, —CN or —NO₂ group, orR¹ and R², together with the C atom to which they are attached arelinked to form an optionally substituted cycloalkyl, cycloalkenyl orheterocycloaliphatic group and n is zero or the integer 1; or is (2)—(X^(a))_(n)Alk′Ar′, or —Alk′X^(a)Ar′ where X^(a) is a group X, Ar′ isan optionally substituted heterocycloaliphatic, or an optionallysubstituted monocyclic or bicyclic aryl group optionally containing oneor more heteroatoms selected from oxygen, sulphur or nitrogen atoms,Alk′ is an optionally substituted straight or branched alkylene,alkenylene or alkynylene chain optionally interrupted by one or more L¹atoms or groups [where L¹ is a linker atom or group] and n is zero orthe integer 1; or is (3) X^(a)R′ where R′ is Ar′ or is an optionallysubstituted polycycloalkyl or polycycloalkenyl group optionallycontaining one or more —O—, or —S— atoms or —N(R^(b))— groups;

Z is a group (A), (B), (C) or (D):

 wherein

Ar is a monocyclic or bicyclic aryl group optionally containing one ormore heteroatoms selected from oxygen, sulphur or nitrogen atoms;

Z¹ is a group —NR¹²C(O)— [where R¹² is a hydrogen atom or an optionallysubstituted alkyl or (Alk)_(t)Ar group], —C(O)NR¹²—, —NR¹²C(S)—,—C(S)NR¹²—, —C≡C—, —NR¹²SO₂—, or —SO₂NR¹²—;

Alk is an optionally substituted straight or branched alkyl chainoptionally interrupted by an atom or group X;

t is zero or an integer of value 1, 2 or 3;

R³ is a hydrogen or a fluorine atom or an optionally substitutedstraight or branched alkyl group or an OR¹¹ group [where R¹¹ is ahydrogen atom or an optionally substituted alkyl, alkenyl, alkoxyalkyl,alkanoyl, formyl, carboxamido or thiocarboxamido group];

R⁴ is a hydrogen atom or an optionally substituted alkyl, —CO₂R⁸,—CSNR⁹R¹⁰, —CN, —CH₂CN, or —(CH₂)_(t)Ar group where t is zero or aninteger of value 1, 2 or 3 and Ar is a monocyclic or bicyclic aryl groupoptionally containing one or more heteroatoms selected from oxygen,sulphur or nitrogen atoms, provided that when L is a group of type (2)or (3) above then Z is a group of type (A) or type (B) in which R⁴ is a—(CH₂)_(t)Ar group;

R⁵ is a group —(CH₂)_(t)Ar;

R⁶ is a hydrogen or a fluorine atom, or an optionally substituted alkylor —CO₂R⁸, —CONR⁹R¹⁰, —CSNR⁹R¹⁰, —CN or —CH₂CN group;

R⁷ is a hydrogen or a fluorine atom, an optionally substituted straightor branched alkyl group, or an OR^(c) group where R^(c) is a hydrogenatom or an optionally substituted alkyl or alkenyl group, alkoxyalkyl,alkanoyl, formyl, carboxamido or thiocarboxamido group; and the salts,solvates, hydrates, prodrugs and N-oxides thereof.

It will be appreciated that certain compounds of formula (1) may haveone or more chiral centres, depending on the nature of the groups Alk,R¹, R², R³, R⁴, R⁵, R⁶ and R⁷. Where one or more chiral centres ispresent, enantiomers or diastereomers may exist, and the invention is tobe understood to extend to all such enantiomers, diastereomers andmixtures thereof, including racemates.

Compounds of formula (1) in which L is a —C(R)═C(R¹)(R²) group and/or Zis the group (B), may exist as geometric isomers depending on the natureof the groups R, R¹, R², R⁴, R⁵ and R⁶, and the invention is to beunderstood to extend to all such isomers and mixtures thereof.

In the compounds of formula (1), when ═W— is ═C(Y)— and Y is a halogenatom Y may be for example a fluorine, chlorine, bromine or iodine atom.

When W in the compounds of formula (1) is a group ═C(Y)— and Y is—XR^(a), R^(a) may be, for example, a hydrogen atom or an optionallysubstituted straight or branched alkyl group, for example, an optionallysubstituted C₁₋₆alkyl group, such as a methyl, ethyl, n-propyl ori-propyl group. Optional substituents which may be present on R^(a)groups include one or more halogen atoms, e.g. fluorine, or chlorineatoms. Particular R^(a) groups include for example —CH₂F, —CH₂Cl, —CHF₂,—CHCl₂, —CF₃ or —CCl₃ groups.

When ═W— in the compounds of formula (1) is a group ═C(Y)— where —Y is—N(R^(b)), ═W— may be a ═C(NH₂)—, ═C(NHCH₃)— or ═C(NHC₂H₅)— group.

In compounds of formula (1), X may be an oxygen or a sulphur atom, or agroup —S(O)—, —S(O)₂—, —NH— or C₁₋₆ alkylamino, for example a C₁₋₃alkylamino, e.g. methylamino [—N(CH₃)—] or ethylamino [—N(C₂H₅)—] group.

Alkyl groups represented by Y, R¹, R² or R^(b) in the compounds offormula (1) include optionally substituted straight or branched C₁₋₆alkyl groups optionally interrupted by one or more X atoms or groups.Particular examples include C₁₋₃ alkyl groups such as methyl, ethyl,n-propyl or i-propyl groups. Optional substituents on these groupsinclude one, two or three substituents selected from halogen atoms, e.g.fluorine, chlorine, bromine or iodine atoms, or hydroxyl or C₁₋₆ alkoxye.g. C₁₋₃ alkoxy such as methoxy or ethoxy or —CO₂R⁸, —CONR⁹R¹⁰,—CSNR⁹R¹¹ or —CN groups. Particular substituted alkyl groups include forexample —CH₂F, —CH₂Cl, —CHF₂, CHCl₂, —CF₃ or —CCl₃ groups.

Alkenyl groups represented by R¹ or R² in the compounds of formula (1)include optionally substituted straight or branched C₂₋₆alkenyl groupsoptionally interrupted by one or more X atoms or groups. Particularexamples include ethenyl, propen-1-yl and 2-methylpropen-1-yl groups.Optional substituents include those described above in relation to alkylgroups represented by the groups R¹ or R².

Alkynyl groups represented by R¹ or R² in compounds of formula (1)include optionally substituted straight or branched C₂₋₆alkynyl groupsoptionally interrupted by one or more X atoms or groups. Particularexamples include ethynyl and propyn-1-yl groups. Optional substituentsinclude those described above in relation to alkyl groups represented bythe groups R¹ or R².

When R¹ or R² in compounds of formula (1) is an alkoxy or alkylthiogroup it may be for example an optionally substituted C₁₋₆alkoxy orC₁₋₆alkylthio group optionally interrupted by one or more X atoms orgroups. Particular examples include C₁₋₃alkoxy, e.g. methoxy or ethoxy,or C₁₋₃alkylthio e.g. methylthio or ethylthio groups. Optionalsubstituents include those described above in relation to alkyl groupsrepresented by the groups R¹ or R².

When R¹ and R² together with the carbon atom to which they are attachedin the compounds of formula (1) are linked to form a cycloalkyl orcycloalkenyl group, the group may be for example a C₃₋₈cycloalkyl groupsuch as a cyclobutyl, cyclopentyl or cyclohexyl group or a C₃₋₈cycloalkenyl group containing for example one or two double bonds suchas a 2-cyclobuten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl,2,4-cyclopentadien-1-yl, 2-cyclohexen-1-yl, 3-cyclohexen-1-yl,2,4-cyclohexadien-1-yl or 3,5-cyclohexadien-1-yl group, each cycloalkylor cycloalkenyl group being optionally substituted by one, two or threesubstituents selected from halogen atoms, e.g. fluorine, chlorine,bromine or iodine atoms, straight or branched C₁₋₆alkyl e.g. C₁₋₃alkylsuch as methyl or ethyl, hydroxyl or C₁₋₆alkoxy e.g. C₁₋₃alkoxy such asmethoxy or ethoxy groups.

The linker atoms represented by the group L¹ include for example —O— or—S— atoms. Particular groups represented by the linker group L¹ are—S(O)—, —S(O)₂—, —N(R^(b))—, —C(O)—, —C(O)₂—, —C(S)—, —C(NR^(b))——CON(R^(b))—, —CSN(R^(b))—, —N(R^(b))CO—, —N(R^(b))CS—, —SON(R^(b))—,—SO₂N(R^(b))—, —N(R^(b))SO—, —N(R^(b))SO₂—, —N(R^(b))SO₂N(R^(b))—,—N(R^(b))SON(R^(b))—, —N(R^(b))CON(R^(b))— or —N(R^(b))CSN(R^(b))—groups. It will be appreciated that when the chain Alk is interrupted bytwo or more L¹ atoms or groups, such atoms or groups may be adjacent toone another, for example to form a group —N(R^(b))—C(NR^(b))—N(R^(b))—or —O—CONH—.

When L is a —(X^(a))_(n)Alk′Ar′ or Alk′X^(a)Ar′ group where Alk′ is analkylene chain L may be for example an optionally substituted straightor branched C₁₋₈alkylene chain optionally interrupted by one or more L¹linker atoms or groups. Particular examples include —CH₂Ar′, —(CH₂)₂Ar′,—OAr′, —SAr′, —N(R^(b))Ar′, —C(O)Ar′, —C(S)Ar′, —CON(R^(b))Ar′, —CSN(R^(b))Ar′, —SOAr′, —SON(R^(b))Ar′, —SO₂Ar′, —SO₂N(R^(b))Ar′, OCH₂Ar′,—SCH₂Ar′, —N(R^(b))CH₂Ar′, —CH₂OAr′, —CH₂SAr′, —CH₂N(R^(b))Ar′,—CH₂C(O)Ar′, —CH₂C(S)Ar′, —CH₂CON(R^(b))Ar′, —CH₂CSN(R^(b))Ar′,—CH₂SOAr′, —CH₂SO₂Ar′, —(CH₂)₂OCH₂Ar′, —(CH₂)₂SCH₂Ar′, —(CH₂)₂SOCH₂Ar′,—(CH₂)₂SO₂CH₂Ar′, —(CH₂)₃Ar′, —O(CH₂)₃Ar′, —S(CH₂)₃Ar′,—N(R^(b))(CH₂)₃Ar′, —SO(CH₂)₃Ar′, —SO₂(CH₂)₃Ar′, —(CH₂)₃OAr′,—(CH₂)₃SAr′, —(CH₂)₃N(R^(b))Ar′, —(CH₂)₃SOAr′ or —(CH₂)₃SO₂Ar′ group.Optional substituents on these groups include those mentioned above inrelation to the alkyl groups represented by Y, R¹, R² or R^(b).

When L is a —(X^(a))_(n)Alk′Ar′ or Alk′X^(a)Ar′ group where Alk′ is analkenylene chain it may be an optionally substituted straight orbranched mono or polyunsaturated C₂₋₈alkenylene chain optionallyinterrupted by one or more L¹ linker atoms or groups. Particularexamples include —(CH═CH)Ar′, —CH═CH—CH₂Ar′, —CH₂—CH═CHAr′,—CH═CH—CH₂Ar′, —OCH═CH—CH₂Ar′, —OCH₂—CH═CHAr′, —SCH═CH—CH₂Ar′,—SCH₂—CH═CHAr′, —N(R^(b))CH═CH—CH₂Ar′, —CH═CH—CH₂—OAr′, —CH₂—CH═CH₂—OAr′or —CH═CH—CH═CHAr′ group. Optional substituents on these groups includethose mentioned above in relation to the alkyl groups represented by Y,R¹, R² or R^(b).

When L is a (X^(a))_(n)Alk′Ar′ or Alk′X^(a)Ar′ group where Alk′ is analkynylene chain, it may be an optionally substituted straight orbranched mono or polyunsaturated C₂₋₈alkynylene chain optionallyinterrupted by one or more L¹ linker atoms or groups. Particularexamples include —C≡CAr′, —C≡C—CH₂Ar′, —CH₂—C≡C—Ar′, —OC≡C—CH₂Ar′,—OCH₂—C≡CAr′, —SC≡C—CH₂Ar′, —SCH₂—C≡CAr′, —N(R^(b))C≡C—CH₂Ar′,—N(R^(b))CH₂—C≡CAr′, —C≡C—CH₂OAr′, —CH₂—C≡COAr′, —C≡C—CH₂SAr′,—CH₂—C≡CSAr′, —CH₂—C≡CN(R^(b))Ar′ or —C≡C—CH₂N(R^(b))Ar′ group. Optionalsubstituents on these groups include those mentioned above in relationto the alkyl groups represented by Y, R¹, R² or R^(b).

When R¹ and R², together with the C atom to which they are attached arelinked to form an optionally substituted heterocycloaliphatic group,and/or when Ar′ is a heterocycloaliphatic group, the group may be forexample an optionally substituted C₃₋₈ cycloalkyl or C₃₋₈ cycloalkenylgroup containing one or more —O—, or —S— atoms, or —N(R^(b))— groupssuch as a pyrrolidinyl, dioxolanyl, e.g. 1,3-dioxolanyl, imidazolidinyl,pyrazolidinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl,thiomorpholinyl, piperazinyl, 1,3,5-trithianyl, 3-pyrrolinyl,2-imidazolinyl, or 2-pyrazolinyl group. Optional substituents which maybe present on such groups include one, two or three substituentsselected from halogen atoms, e.g. fluorine, chlorine, bromine or iodineatoms, straight or branched C₁₋₆ alkyl e.g. C₁₋₃ alkyl such as methyl orethyl, hydroxyl or C₁₋₆ alkoxy e.g. C₁₋₃ alkoxy such as methoxy orethoxy groups.

Polycycloalkyl groups represented by R′ in compounds of formula (1)include optionally substituted C₆₋₁₀ polycycloalkyl, e.g. bicycloalkylor tricycloalkyl groups optionally containing one, two or more —O— or—S— atoms or —N(R^(b))— groups. Polycycloalkenyl groups represented byAr′include optionally substituted C₆₋₁₀ polycycloalkenyl, e.g.bicycloalkenyl or tricycloalkenyl groups optionally containing one, twoor more—O— or —S— atoms or —N(R^(b)) groups. The degree of unsaturationof polycycloalkenyl groups may be varied widely and the term is to beunderstood to include groups with one, two, three or more —CH═CH—groups. Optional substituents which may be present on such groupsinclude those mentioned above in relation to the Ar′ group when Ar′ is ahetero-cycloaliphatic group.

When the group R⁷ in compounds of formula (1) is an OR^(c) group it maybe for example a hydroxyl group; or a group —OR^(c) where R^(c) is anoptionally substituted straight or branched C₁₋₆alkyl group, e.g. aC₁₋₃alkyl group such as a methyl or ethyl group, a C₂₋₆alkenyl groupsuch as an ethenyl or 2-propen-1-yl group, a C₁₋₃alkoxyC₁₋₃alkyl groupsuch as a methoxymethyl, ethoxymethyl or ethoxyethyl group, aC₁₋₆alkanoyl, e.g. C₁₋₃alkanoyl group such as an acetyl group, or aformyl [HC(O)—], carboxamido (CONR¹³R^(13a)) or thiocarboxamido(CSNR¹³R^(13a)) group, where R¹³ and R^(13a) in each instance may be thesame or different and is each a hydrogen atom or an optionallysubstituted straight or branched C₁₋₆alkyl, e.g. C₁₋₃alkyl group such asmethyl or ethyl group. Optional substituents which may be present onsuch R^(c), R¹³ or R^(13a) groups include those described below inrelation to the alkyl groups R³, R⁴, R⁶, R⁷ and R¹².

Alkyl groups represented by R³, R⁴, R⁶, R⁷ or R¹² in compounds offormula (1) include optionally substituted straight or branched C₁₋₆alkyl groups, e.g. C₁₋₃ alkyl groups such as methyl, ethyl, n-propyl ori-propyl groups. Optional substituents which may be present on thesegroups include one or more halogen atoms, e.g. fluorine, chlorine,bromine or iodine atoms, or hydroxyl or C₁₋₆alkoxy e.g. C₁₋₃alkoxy suchas methoxy or ethoxy groups.

When R¹, R², R⁴ or R⁶ is a —CO₂R⁸, —CONR⁹R¹⁰ or CSNR⁹R¹⁰ group it may befor example a —CO₂H, —CONH₂ or —CSNH₂ group or a group —CO₂R⁸,—CONR⁹R¹⁰, —CSNR⁹R¹⁰, —CONHR¹⁰, or —CSNHR¹⁰ where R⁸, R⁹ and R¹⁰ wherepresent is a C₁₋₃alkyl group such as methyl or ethyl group, a C₆₋₁₂arylgroup, for example an optionally substituted phenyl, or a 1- or2-naphthyl group, or a C₆₋₁₂aryl C₁₋₃alkyl group such as an optionallysubstituted benzyl or phenethyl group. Optional substituents which maybe present on these aryl groups include R¹⁴ substituents discussed belowin relation to the group Ar.

When the chain Alk is present in compounds of formula (1) it may be anoptionally subtituted straight or branched C₁₋₃alkylene chain optionallyinterrupted by an atom or group X. Particular examples include —CH₂—,—(CH₂)₂—, —(CH₂)₃—, —CH₂OCH₂—, —CH₂SCH₂—, or —CH₂N(R^(b))CH₂, e.g.—CH₂NHCH₂— or —CH₂N(CH₃)CH₂— chains. Optional substituents include thosedescribed in relation to the alkyl groups represented by R³, R⁴, R⁶, R⁷and R¹².

In the compounds of formula (1) when the group —(Alk)_(t)(X)_(n)Ar ispresent it may be a group —Ar, —CH₂Ar, —(CH₂)₂Ar, —(CH₂)₃Ar, —CH₂OAr,—CH₂OCH₂Ar, —CH₂N(R^(b))Ar or —CH₂N(R^(b))CH₂Ar group.

Monocyclic or bicyclic aryl groups represented by the group Ar, Ar′, orR′ in compounds of formula (1) include for example C₆₋₁₂ optionallysubstituted aryl groups, for example optionally substituted phenyl, 1-or 2-naphthyl, indenyl or isoindenyl groups.

When the monocyclic or bicyclic aryl group Ar, Ar′ or R′ contains one ormore heteroatoms it may be for example a C₅₋₁₀ optionally substitutedheteroaryl group containing for example one, two, three or fourheteroatoms selected from oxygen, sulphur or nitrogen atoms. In general,Ar heteroaryl groups may be for example monocyclic or bicyclicheteroaryl groups. Monocyclic heteroaryl groups include for examplefive- or six-membered heteroaryl groups containing one, two, three orfour heteroatoms selected from oxygen, sulphur or nitrogen atoms.Bicyclic heteroaryl groups include for example nine- or ten-memberedheteroaryl groups containing one, two or more heteroatoms selected fromoxygen, sulphur or nitrogen atoms.

Examples of heteroaryl groups represented by Ar, Ar′ or R′ includepyrrolyl, furyl, thienyl, imidazolyl, N-methylimidazolyl,N-ethylimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl,pyrimidinyl, pyridazinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl,1,2,3-triazinyl, benzofuryl, isobenzofuryl, benzothienyl,isobenzothienyl, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl,benzoxazolyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridyl,pyrido[3,2-b]pyridyl, pyrido[4,3-b]pyridyl, quinolinyl, isoquinolinyl,tetrazolyl, 5,6,7,8-tetrahydroquinolinyl and5,6,7,8-tetrahydroisoquinolinyl. Example of bicyclic heteroaryl groupsinclude quinolinyl or isoquinolinyl groups.

The heteroaryl group represented by Ar, Ar′ or R′ may be attached to theremainder of the molecule of formula (1) through any ring carbon orheteroatom as appropriate. Thus, for example, when the group Ar or Ar′is a pyridyl group it may be a 2-pyridyl, 3-pyridyl or 4-pyridyl group.When it is a thienyl group it may be a 2-thienyl or 3-thienyl group,and, similarly, when it is a furyl group it may be a 2-furyl or 3-furylgroup. In another example, when the group Ar is a quinolinyl group itmay be a 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl and when it is anisoquinolinyl, it may be a 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinylgroup.

When in compounds of formula (1) the Ar, Ar′ or R′ group is anitrogen-containing heterocycle it may be possible to form quaternarysalts, for example N-alkyl quaternary salts and the invention is to beunderstood to extend to such salts. Thus for example when the group Aris a pyridyl group, pyridinium salts may be formed, for exampleN-alkylpyridinium salts such as N-methylpyridinium.

The aryl or heteroaryl groups represented by Ar, Ar′ or R′, in compoundsof formula (1) may each optionally be substituted by one, two, three ormore substituents [R¹⁴]. The substituent R¹⁴ may be selected from anatom or group R¹⁵ or —Alk¹(R¹⁵)_(m) wherein R¹⁵ is a halogen atom, or anamino (—NH₂), substituted amino, nitro, cyano, hydroxyl (—OH),substituted hydroxyl, cycloalkoxy, cycloaliphatic, formyl [HC(O)—],carboxyl (—CO₂H), esterified carboxyl, thiol (—SH), substituted thiol,—C(O)R″ [where R″ is a group Alk¹ where Alk¹ is a straight or branchedC₁₋₆ alkylene, C₂₋₆alkenylene, or C₂₋₆alkynylene chain optionallyinterrupted by one, two, or three —O—, or —S— atoms or —S(O)_(z)—,(where z is an integer 1 or 2) or —N(R^(b))— groups; or is a group Ar″(where Ar″ is as defined for Ar), —SO₃H, —SO₂R″, —SO₂NH₂, —SO₂NHR″—SO₂N[R″]₂, —CONH₂, —CONHR″ —CON[R″]₂, —NHSO₂H, —N(R″)SO₂H, —NHSO₂R″,—NR″SO₂R″, —N[SO₂R″]₂, —NHSO₂NH₂, —NR″SO₂NH₂, —NHSO₂NHR″, —NR″SO₂NHR″,—NR″SO₂NHR″, —NHSO₂N[R″]₂, —N(R″)SO₂N[R″]₂, —NHC(O)R″, —NR″C(O)R″,—N[C(O)R″]₂, —NHC(O)H, —NR″C(O)H, —NHC(O)OR″, —NR″C(O)OR″, —NHC(O)OH,—NR″C(O)OH, —NHCONH₂, —NHCONHR″, —NHCON[R″]₂, —NR″CON[R″]₂, —C(S)R″,—C(S)NH₂, —C(S)NHR″, —C(S)N[R″]₂, —NHC(S)R″, —NR″C(S)R″, —N[[C(S)R″]₂,—NHC(S)H, —NR″C(S)H, —NHC(S)NH₂, —NHC(S)NHR″, —NHC(S)N[R″]₂,—NR″C(S)N[R″]₂, —Ar″ or —XAr″ group; and m is zero or an integer 1, 2 or3.

When in the group —Alk¹(R¹⁵)_(m) m is an integer 1, 2 or 3, it is to beunderstood that the substituent or substituents R¹⁵ may be present onany suitable carbon atom in —Alk¹. Where more than one R¹⁵ substituentis present these may be the same or different and may be present on thesame or different carbon atom in Alk¹. Clearly, when m is zero and nosubstituent R¹⁵ is present or when Alk¹ forms part of a group such as—SO₂Alk¹ the alkylene, alkenylene or alkynylene chain represented byAlk¹ becomes an alkyl, alkenyl or alkynyl group.

When R¹⁵ is a substituted amino group it may be a group—NH[Alk¹(R^(15a))_(m)] [where Alk¹ and m are as defined above andR^(15a) is as defined above for R¹⁵ but is not a substituted amino, asubstituted hydroxyl or a substituted thiol group] or a group—N[Alk¹(R^(15a))_(m]2) wherein each —Alk¹(R^(15a))_(m) group is the sameor different.

When R¹⁵ is a halogen atom it may be for example a fluorine, chlorine,bromine, or iodine atom.

When R¹⁵ is a cycloalkoxy group it may be for example a C₅₋₇cycloalkoxygroup such as a cyclopentyloxy or cyclohexyloxy group.

When R¹⁵ is a substituted hydroxyl or substituted thiol group it may bea group —OAlk¹(R^(15a))_(m) or —SAlk¹(R^(15a))_(m) respectively, whereAlk¹, R^(15a) and m are as just defined.

Esterified carboxyl groups represented by the group R¹⁵ include groupsof formula —CO₂Alk² wherein Alk² is a straight or branched, optionallysubstituted C₁₋₈alkyl group such as a methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl or t-butyl group; a C₆₋₁₂arylC₁₋₈alkyl groupsuch as an optionally substituted benzyl, phenylethyl, phenylpropyl,1-naphthylmethyl or 2-naphthylmethyl group; a C₆₋₁₂aryl group such as anoptionally substituted phenyl, 1-naphthyl or 2-naphthyl group; aC₆₋₁₂aryloxyC₁₋₈alkyl group such as an optionally substitutedphenyloxymethyl, phenyloxyethyl, 1-naphthyloxymethyl, or2-naphthyloxymethyl group; an optionally substitutedC₁₋₈alkanoyloxyC₁₋₈alkyl group, such as a pivaloyloxymethyl,propionyloxyethyl or propionyloxypropyl group; or aC₆₋₁₂aroyloxyC₁₋₈alkyl group such as an optionally substitutedbenzoyloxyethyl or benzoyloxy-propyl group. Optional substituentspresent on the Alk² group include R¹⁴ substituents described above.

When the group R¹⁵ in compounds of formulae (1) and (2) is an optionallysubstituted C₃₋₉cycloaliphatic group, it may be a C₃₋₉cycloalkyl orC₃₋₉cycloalkenyl group such as a C₅₋₇cycloalkyl or C₅₋₇cycloalkenylgroup, containing 1, 2, 3 or more heteroatoms selected from oxygen,sulphur or nitrogen atoms. Particular examples of such R¹⁵ groupsinclude pyrrolyl, e.g. 2H-pyrrolyl, pyrrolinyl, e.g. 2- or 3-pyrrolinyl,pyrrolidinyl, 1,3-dioxolanyl, imidazolinyl, e.g. 2-imidazolinyl,imidazolidinyl, pyrazolinyl, e.g. 2-pyrazolinyl, pyrazolidinyl, pyranyl,e.g. 2- or 4-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl,1,4-dithianyl, thiomorpholinyl, piperazinyl, 1,3,5-trithianyl,3H-pyrrolyl, 2H-imidazolyl, dithiolyl, e.g. 1,2- or 1,3-dithiolyl,oxathiolyl, e.g. 3H-1-2 or 1,3-oxathiolyl, 5H-1,2,5-oxathiozolyl,1,3-dioxinyl, oxazinyl, e.g. 2H-1,3-, 6H-1,3-, 6H-1,2-, 1,4-2H-1,2- or4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, isoxazinyl, e.g. -o- orp-isoxazinyl, oxathiazinyl, e.g. 1,2,5-, 1,2,6-oxathiazinyl,1,3,5,2-oxadiazinyl, or 1,2,4-diazepinyl groups. Optional substituentswhich may be present on such groups include those substituents discussedabove in relation to the group Ar′ where Ar′ is a heterocycloaliphaticgroup.

It will be appreciated that the group Ar, Ar′ or R′ may be attached tothe remainder of the molecule of formula (1) through either a ringcarbon atom or heteroatom.

Particular examples of the group Alk¹ when present include methylene,ethylene, n-propylene, i-propylene, n-butylene, i-butylene, s-butylene,t-butylene, ethenylene, 2-propenylene, 2-butenylene, 3-butenylene,ethynylene, 2-propynylene, 2-butynylene or 3-butynylene chain,optionally interrupted by one, two, or three —O— or —S— atoms or —S(O)—,—S(O)₂— or —N(R^(b))— groups.

Particularly useful atoms or groups represented by R¹⁴ include fluorine,chlorine, bromine or iodine atoms, or C₁₋₆alkyl, e.g. methyl or ethyl,C₁₋₆alkylamino, e.g. methylamino or ethylamino, C₁₋₆ hydroxyalkyl, e.g.hydroxymethyl or hydroxyethyl, C₁₋₆alkylthiol e.g. methylthiol orethylthiol, C₁₋₆alkoxy, e.g. methoxy or ethoxy, C₅₋₇cycloalkyl e.g.cyclopentyl, C₅₋₇ cycloalkoxy, e.g. cyclopentyloxy, haloC₁₋₆alkyl, e.g.trifluoromethyl, C₁₋₆ alkylamino, e.g. methylamino or ethylamino, amino(—NH₂), aminoC₁₋₆alkyl, e.g. aminomethyl or aminoethyl,C₁₋₆dialkylamino, e.g. dimethylamino or diethylamino, nitro, cyano,hydroxyl (—OH), formyl [HC(O)—], carboxyl (—CO₂H), —CO₂Alk² [where Alk²is as defined above], C₁₋₆ alkanoyl e.g. acetyl, thiol (—SH),thioC₁₋₆alkyl, e.g. thiomethyl or thioethyl, sulphonyl (—SO₃H),C₁₋₆alkylsulphonyl, e.g. methylsulphonyl, aminosulphonyl (—SO₂NH₂),C₁₋₆alkylaminosulphonyl, e.g. methylaminosulphonyl orethyl-aminosulphonyl, C₁₋₆dialkylaminosulphonyl, e.g.dimethylaminosulphonyl or diethylaminosulphonyl, phenylaminosulphonyl,carboxamido (—CONH₂), C₁₋₆alkylaminocarbonyl, e.g. methylaminocarbonylor ethylaminocarbonyl, C₁₋₆dialkylaminocarbonyl, e.g.dimethylaminocarbonyl or diethylaminocarbonyl, phenylaminocarbonyl,sulphonylamino (—NHSO₂H), C₁₋₆alkylsulphonylamino, e.g.methylsulphonylamino or ethylsulphonylamino, C₁₋₆ dialkylsulphonylamino,e.g. dimethylsulphonylamino or diethylsulphonylamino,aminosulphonylamino (—NHSO₂NH₂), C₁₋₆alkylaminosulphonylamino, e.g.methylaminosulphonylamino or ethylaminosulphonylamino,C₁₋₆dialkylaminosulphonylamino, e.g. dimethylaminosulphonylamino ordiethylaminosulphonylamino, phenylam inosulphonylamino,C₁₋₆alkanoylamino, e.g. acetylamino, C₁₋₆alkanoylaminoC₁₋₆alkyl, e.g.acetylaminomethyl or C₁₋₆ alkoxycarbonylamino, e.g.methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino,thiocarboxamido (—CSNH₂), C₁₋₆ alkylaminothiocarbonyl, e.g.methylaminothiocarbonyl or ethylaminothiocarbonyl,C₁₋₆dialkylaminothiocarbonyl, e.g. dimethylaminothiocarbonyl ordiethylaminothiocarbonyl, aminocarbonylamino,C₁₋₆alkylaminocarbonylamino, e.g. methylaminocarbonylamino orethylaminocarbonylamino, C₁₋₆dialkylaminocarbonylamino, e.g.dimethylaminocarbonylamino or diethylaminocarbonylamino,aminothiocarbonylamino, C₁₋₆alkylaminothiocarbonylamino, e.g.methylaminothiocarbonylamino or ethylaminothiocarbonylamino, C₁₋₆dialkylaminothiocarbonylamino, e.g. dimethylaminothiocarbonylamino, ordiethylaminothiocarbonylamino, aminocarbonylC₁₋₆alkylamino, e.g.aminocarbonylmethylamino or aminocarbonylethylamino,aminothiocarbonylC₁₋₆alkylamino e.g. aminothiocarbonylmethylamino oraminothiocarbonylethylamino, formylaminoC₁₋₆ alkylsulphonylamino, e.g.formylaminomethylsulphonylamino or formylaminoethylsulphonylamino,thioformylaminoC₁₋₆alkylsulphonylamino, e.g.thioformylaminomethylsulphonylamino or thioformylethylsulphonylamino,C₁₋₆acylaminosulphonylamino, e.g. acetylaminosulphonylamino,C₁₋₆thioacylaminosulphonylamino, e.g. thioacetylaminosulphonylaminogroups, —Ar″, e.g. phenyl, —XAr″ e.g. phenoxy, or —Alk¹Ar″ e.g. benzylor phenethyl groups.

Where desired, two R¹⁴ substituents may be linked together to form acyclic group such as a cyclic ether, e.g. a C₂₋₆alkylenedioxy group suchas ethylenedioxy.

It will be appreciated that where two or more R¹ ⁴ substituents arepresent, these need not necessarily be the same atoms and/or groups. TheR¹⁴ substituents may be present at any ring carbon atom away from thatattached to the rest of the molecule of formula (1). Thus, for example,in phenyl groups represented by Ar any substituent may be present at the2-, 3-, 4-, 5- or 6-positions relative to the ring carbon atom attachedto the remainder of the molecule.

Particular examples of the chain Z¹ in compounds of formula (1) include—NHCO—, —CONH—, —NHCS—, —CSNH—, —NHSO₂—, —SO₂NH— and —C═C—.

In the compounds of formula (1), when an ester group is present, forexample a group —CO₂R⁸ or —CO₂Alk² this may advantageously be ametabolically labile ester.

The presence of certain substituents in the compounds of formula (1) mayenable salts of the compounds to be formed. Suitable salts includepharmaceutically acceptable salts, for example acid addition saltsderived from inorganic or organic acids, and salts derived frominorganic and organic bases.

Acid addition salts include hydrochlorides, hydrobromides, hydroiodides,alkylsulphonates, e.g. methanesulphonates, ethanesulphonates, orisethionates, arylsulphonates, e.g. p-toluenesulphonates, besylates ornapsylates, phosphates, sulphates, hydrogen sulphates, acetates,trifluoroacetates, propionates, citrates, maleates, fumarates,malonates, succinates, lactates, oxalates, tartrates and benzoates.

Salts derived from inorganic or organic bases include alkali metal saltssuch as sodium or potassium salts, alkaline earth metal salts such asmagnesium or calcium salts, and organic amine salts such as morpholine,piperidine, dimethylamine or diethylamine salts.

Prodrugs of compounds of formula (1) include those compounds, forexample esters, alcohols or aminos, which are convertible in vivo bymetabolic means, e.g. by hydrolysis, reduction, oxidation ortrans-esterification, to compounds of formula (1).

Particularly useful salts of compounds according to the inventioninclude pharmaceutically acceptable salts, especially acid additionpharmaceutically acceptable salts.

In the compounds of formula (1) the group ═W— is preferably a ═C(Y)—group. In compounds of this type Y is preferably a —XR^(a) group where Xis —O— and R^(a) is an optionally substituted ethyl group or,especially, an optionally substituted methyl group. Especially usefulsubstituents which may be present on R^(a) groups include one, two orthree fluorine or chlorine atoms.

The group L in compounds of formula (1) is preferably a —CH═C(R¹)(R²)group. In compounds of this type R¹ and R² are preferably linkedtogether with the C atom to which they are attached to form anoptionally substituted cycloalkyl or cycloalkenyl group, especially asubstituted cyclopentyl or cyclohexyl or, especially, a cyclopentyl orcyclohexyl group.

In the compounds of formula (1) where Z is the group (A), one preferredgroup of compounds are those where the group R³ is a hydrogen atom; thegroup R⁶ is a methyl group, or especially a hydrogen atom; the group R⁷is a methyl group, or especially a hydrogen atom; and R⁴ and R⁵ are asdefined for formula (1). In compounds of this type R⁶ and R⁷ in onepreference, is each a methyl group; in another preference, one of R⁶ orR⁷ is a methyl group and the other is a hydrogen atom, in general,however, R⁶ and R⁷ is each especially a hydrogen atom.

The groups R⁴ and R⁵ when present in compounds of formula (1) are each,independently, preferably a —CH₂Ar group, or, especially, an —Ar group.Particularly useful R⁴ or R⁵ groups of this type include those groups inwhich Ar is a monocyclic aryl group optionally containing one or moreheteroatoms selected from oxygen, sulphur, or, in particular, nitrogenatoms, and optionally substituted by one, two, three or more R¹⁴substituents. In these compounds, when the group represented by Ar is aheteroaryl group it is preferably a nitrogen-containing monocyclicheteroaryl group, especially a six-membered nitrogen-containingheteroaryl group. Thus, in one preferred example, the groups R⁴ and R⁵may each be a six-membered nitrogen-containing heteroaryl group. Inanother preferred example R⁴ may be a monocyclic aryl group or amonocyclic or bicyclic heteroaryl group containing one or more oxygen,sulphur or nitrogen atom and R⁵ may be a six-memberednitrogen-containing heteroaryl group. In these examples, thesix-membered nitrogen-containing heteroaryl group may be an optionallysubstituted pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or imidazolylgroup. Particular examples include optionally substituted 2-pyridyl,3-pyridyl, 5-imidazolyl, or, especially, 4-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 2-pyrazinyl or 3-pyrazinyl. The monocyclic aryl group maybe a phenyl group or a substituted phenyl group, and the monocyclic orbicyclic heteroaryl group containing one or more oxygen, sulphur ornitrogen atom may be an optionally substituted 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-thiazolyl, 2-benzo(b)thiophenyl, 2-benzo(b)furylor 4-isoquinolinyl group.

One particularly useful group of compounds of formula (1) when Z is agroup (A) or (B) is that wherein R⁴ and R⁵ is each a pyridyl or,especially, a monosubstituted pyridyl, or preferably a disubstitutedpyridyl group, or R⁴ is a phenyl, thienyl or furyl, or substitutedphenyl, thienyl or furyl group and R⁵ is a pyridyl or, especially amonosubstituted pyridyl, or preferably a disubstituted pyridyl group.

In this particular group of compounds and also in general in compoundsof formula (1) when R⁴ and/or R⁵ is a substituted phenyl group it may befor example a mono-, di- or trisubstituted phenyl group in which thesubstituent is an atom or group R¹⁴ as defined above. When the R⁴ and/orR⁵ group is a monosubstituted phenyl group the substituent may be in the2-, or preferably 3-, or especially 4-position relative to the ringcarbon atom attached to the remainder of the molecule. When the R⁴and/or R⁵ group is a disubstituted phenyl group, the substituents may bein the 2,6 position relative to the ring carbon atom attached to theremainder of the molecule.

When in compounds of formula (1) R⁴ and/or R⁵ is a substituted pyridylgroup it may be for example a mono- or disubstituted pyridyl group, suchas a mono- or disubstituted 2-pyridyl, 3-pyridyl or especially 4-pyridylgroup substituted by one or two atoms or groups R¹⁴ as defined above, inparticular one or two halogen atoms such as fluorine or chlorine atoms,or methyl, methoxy, hydroxyl or nitro groups. Particularly usefulpyridyl groups of these types are 3-monosubstituted-4-pyridyl or3,5-disubstituted-4-pyridyl, or 2- or 4-monosubstituted-3-pyridyl or2,4-disubstituted-3-pyridyl groups.

Other particularly useful groups of compounds of formula (1) where Z isthe group (B), include those where R⁴ is a —CH₃ group or a hydrogenatom; R⁵ is a hydrogen atom, a —CN or a —CH₃ group; R⁶ is as justdescribed for R⁴ and R⁵ in the compounds of formula (1) where Z is thegroup (A).

Another particularly useful group of compounds of formula (1) when Z isa group (C) is that wherein Ar is a phenyl, naphthyl, pyrrolyl, furyl,thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridyl,pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl,5,6,7,8-tetrahydroquinolinyl or 5,6,7,8-tetrahydro-isoquinolinyl group.In compounds of this type when Ar is a quinolinyl group it may be forexample a mono- or disubstituted quinolinyl group such as a2-monosubstituted-4-quinolinyl group; when it is a pyridyl group, it maybe an optionally substituted 3- or 4-pyridyl, e.g. a2,3,5,6-tetrasubstituted-4-pyridyl or 2,4,6-trisubstituted-3-pyridylgroup; when it is a pyrimidinyl group, it may be for example a5-pyrimidinyl group or a 2-substituted 5-pyrimidinyl group; and when itis an isoquinolinyl group, it may be a 4-isoquinolinyl group.

Other especially useful groups of compounds of formula (1) include thosewhere Z is a group (D) in which (1) —Z¹— is a —C(O)NR¹²— group, whereR¹² is a hydrogen atom. In compounds of this type, t is preferably zeroand Ar is a 2-nitrophenyl or 4-(3,5-dichloro)pyridyl group, or (2) thosewhere —Z¹— is a —NR¹²C(O)— group, where R¹² is a hydrogen atom, t iszero and Ar is a 4-pyridyl or 4-(3,5-dichloro)pyridyl, benzyl or2-methylbenzoate group, or t is an integer of value 1 and Ar is a 2- or3-nitrophenyl, phenyl or 2-methylphenyl group.

A particularly useful group of compounds of formula (1) has the formula(2):

where (1) —L is a —CH═C(R¹)(R²) or —CH₂CH(R¹)(R²) group where R¹ and R²are linked together with the carbon atom to which they are attached toform a cycloalkyl group; or (2) L is a group —OAlkAr′ where Alk is aC₁₋₆alkylene chain and Ar′ is a monocyclic aryl or heteroaryl group.Particular examples of such L groups include benzyloxy, thienyloxy orphenylpentyloxy groups; or (3) L is a group OR′ where R′ is anoptionally substituted polycyloalkyl or polycycloalkyl group or is asdescribed above for Ar′. Preferred examples of such R′ groups includeoptionally substituted bicycylo[2.2.1]heptyl or bicyclo[2.2.1]heptenylgroup. In particular R′ is a bicyclo[2.2.1]hept-2-yl group; and Z is asdefined for formula (1); and the salts, solvates, hydrates, prodrugs andN-oxides thereof.

In compounds of formula (2) where R³, R⁶ or R⁷ is present it is eachpreferably a hydrogen atom.

A particularly useful group of compounds according to the invention hasthe formula (2) wherein L is a OR′ group and Z is the group (A). In thisparticular group of compounds R³, R⁶ and R⁷ is each a hydrogen atom andR⁴ and R⁵ are as defined for compounds of formula (1) and the salts,solvates, hydrates and N-oxides thereof. Compounds of this type in whichR′ is a bicyclo[2.2.1]heptyl, particularly a bicyclo[2.2.1]hept-2-ylgroup are particularly useful. In this group of compounds, R⁴ ispreferably a monocyclic aryl group, particularly a phenyl or substitutedphenyl group or R⁴ is a six-membered nitrogen-containing monocyclicheteroaryl group, particularly a pyridyl or substituted pyridyl groupand R⁵ is a six-membered nitrogen-containing monocyclic heteroarylgroup, especially a pyridyl or substituted pyridyl group, in particulara 4-pyridyl or substituted 4-pyridyl group.

Other particularly useful groups of compounds of formulae (1) or (2)where L is a group —C(R)═C(R¹)(R²) or —(X^(a))_(n)Alk′Ar′ and Z is thegroup (B), include those where R⁴ is a —CH₃ group or a hydrogen atom; R⁵is a hydrogen atom, a —CN or a —CH₃ group; R⁶ is as just described forR⁴ and R⁵ in the compounds of formulae (1) or (2) where Z is the group(A).

Particular compounds according to the invention are:

(2R)-4-{2-[3-((2RS)-exo-Bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl]-2-phenylethyl}pyridine;

(±)-4-[2-(3-Benzyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine;

(±)-4-{2-[4-Methoxy-3-(3-thienyloxy)phenyl]-2-phenylethyl}pyridine;

(±)-4-[2-(3-Cyclopentylidenyl-4-methoxyphenyl)-2-phenylethyl]pyridine;

(±)-4-[2-(3-Cyclohexylidenyl-4-methoxyphenyl)-2-phenylethyl]pyridine;

(E,Z)-3-(3-Cyclopentylidenyl-4-methoxyphenyl)-2-(2,6-dichlorophenyl)propenenitrile;

(E,Z)-3-(3-Cyclopentylidenyl-4-methoxyphenyl)-2-(2,6-difluorophenyl)propenenitrile;

(E,Z)-4-[2-(3-Cyclopentylidenyl-4-methoxyphenyl)ethenyl]-3,5-dichloropyridine;

3-(3-Cyclopentylidenyl-4-methoxyphenyl)pyridine;

5-(3-Cyclopentylidenyl-4-methoxyphenyl)pyrimidine;

4-(3-Cyclopentylidenyl-4-methoxyphenyl)nitrobenzene;

3-(3-Cyclopentylmethyl-4-methoxyphenyl)pyridine;

N-(3-Cyclopentylidenyl-4-methoxyphenyl)-3,5-dichloro-4-pyridenecarboxamide;

4-[2-(3-Cyclopentylidenyl-4-methoxyphenyl)ethyl]pyridine;

N-{4-[2-(3-Cyclopentylidenyl-4-methoxyphenyl)ethyl]-3-pyridyl}phenylsulphonamide;

3-Cyclopentylidenyl-4-methoxy-N-(2-nitrobenzoyl)aniline;

N-(3-Cyclopentylidenyl-4-methoxyphenyl)-4-pyridinecarboxamide;

N-Phenyl-3-cyclopentylidenyl-4-methoxybenzamide;

N-(2-Nitrophenyl)-3-cyclopentylidenyl-4-methoxybenzamide;

N-(3,5-Dichloropyrid-4-yl)-3-cyclopentylidenyl-4-methoxybenzamide;

and the salts, solvates, hydrates, prodrugs and N-oxides thereof.

Compounds according to the invention are selective and potent inhibitorsof PDE IV. The ability of the compounds to act in this way may be simplydetermined by the tests described in the Examples hereinafter.Particular uses to which the compounds of the invention may be putinclude the prophylaxis and treatment of asthma, especially inflamedlung associated with asthma, cystic fibrosis, or in the treatment ofinflammatory airway disease, chronic bronchitis, eosinophilic granuloma,psoriasis and other benign and malignant proliferative skin diseases,endotoxic shock, septic shock, ulcerative colitis, Crohn's disease,reperfusion injury of the myocardium and brain, inflammatory arthritis,chronic glomerulonephritis, atopic dermatitis, urticaria, adultrespiratory distress syndrome, diabetes insipidus, allergic rhinitis,allergic conjunctivitis, vernal conjunctivitis, arterial restenosis andartherosclerosis.

Compounds of the invention may also suppress neurogenic inflammationthrough elevation of cAMP in sensory neurones. They are, therefore,analgesic, anti-tussive and anti-hyperalgesic in inflammatory diseasesassociated with irritation and pain.

Compounds according to the invention may also elevate cAMP inlymphocytes and thereby suppress unwanted lymphocyte activation inimmune-based diseases such as rheumatoid arthritis, ankylosingspondylitis, transplant rejection and graft versus host disease.

Compounds according to the invention may also reduce gastric acidsecretion and therefore can be used to treat conditions associated withhypersecretion.

Compounds of the invention may suppress cytokine synthesis byinflammatory cells in response to immune or infectious stimulation. Theyare, therefore, useful in the treatment of bacterial, fungal or viralinduced sepsis and septic shock in which cytokines such as tumournecrosis factor (TNF) are key mediators. Also compounds of the inventionmay suppress inflammation and pyrexia due to cytokines and are,therefore, useful in the treatment of inflammation and cytokine-mediatedchronic tissue degeneration which occurs in diseases such as rheumatoidor osteoarthritis.

Over-production of cytokines such as TNF in bacterial, fungal or viralinfections or in diseases such as cancer, leads to cachexia and musclewasting. Compounds of the invention may ameliorate these symptoms with aconsequent enhancement of quality of life.

Compounds of the invention may also elevate cAMP in certain areas of thebrain and thereby counteract depression and memory impairment.

Compounds of the invention may suppress cell proliferation in certaintumour cells and can be used, therefore, to prevent tumour growth andinvasion of normal tissues.

For the prophylaxis or treatment of disease the compounds according tothe invention may be administered as pharmaceutical compositions, andaccording to a further aspect of the invention we provide apharmaceutical composition which comprises a compound of formula (1)together with one or more pharmaceutically acceptable carriers,excipients or diluents.

Pharmaceutical compositions according to the invention may take a formsuitable for oral, buccal, parenteral, nasal, topical or rectaladministration, or a form suitable for administration by inhalation orinsufflation.

For oral administration, the pharmaceutical compositions may take theform of, for example, tablets, lozenges or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g. lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g. magnesium stearate, talc or silica); disintegrants (e.g. potatostarch or sodium glycollate); or wetting agents (e.g. sodium laurylsulphate). The tablets may be coated by methods well known in the art.Liquid preparations for oral administration may take the form of, forexample, solutions, syrups or suspensions, or they may be presented as adry product for constitution with water or other suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents,emulsifying agents, non-aqueous vehicles and preservatives. Thepreparations may also contain buffer salts, flavouring, colouring andsweetening agents as appropriate.

Preparations for oral administration may be suitably formulated to givecontrolled release of the active compound.

For buccal administration the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds of formulae (1) and (2) may be formulated for parenteraladministration by injection e.g. by bolus injection or infusion.Formulations for injection may be presented in unit dosage form, e.g. inglass ampoule or multi dose containers, e.g. glass vials. Thecompositions for injection may take such forms as suspensions, solutionsor emulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilising, preserving and/or dispersingagents. Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile pyrogen-free water,before use.

In addition to the formulations described above, the compounds offormulae (1) and (2) may also be formulated as a depot preparation. Suchlong acting formulations may be administered by implantation or byintramuscular injection.

For nasal administration or administration by inhalation, the compoundsfor use according to the present invention are conveniently delivered inthe form of an aerosol spray presentation for pressurised packs or anebuliser, with the use of suitable propellant, e.g.dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas ormixture of gases.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack or dispensing device may be accompanied byinstructions for administration.

The quantity of a compound of the invention required for the prophylaxisor treatment of a particular inflammatory condition will vary dependingon the compound chosen, and the condition of the patient to be treated.In general, however, daily dosages may range from around 100 ng/kg to100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight for oral orbuccal administration, from around 10 ng/kg to 50 mg/kg body weight forparenteral administration and around 0.05 mg to around 1000 mg e.g.around 0.5 mg to around 1000 mg for nasal administration oradministration by inhalation or insufflation.

The compounds according to the invention may be prepared by thefollowing processes. The symbols W, L, Z, X,R¹, R², R³, R⁴, R⁵, R⁶, andR⁷ when used in the formulae below are to be understood to representthose groups described above in relation to formula (1) unless otherwiseindicated. In the reactions described below it may be necessary toprotect reactive functional groups, for example hydroxy, amino, thio,carboxy or aldehyde groups, where these are desired in the finalproduct, to avoid their unwanted participation in the reactions.Conventional protecting groups may be used in accordance with standardpractice [see, for example, Green, T. W. in “Protective Groups inOrganic Synthesis” John Wiley and Sons, 1981].

Thus, according to a further aspect of the invention, compounds ofgeneral formula (1) where L is X^(a)Alk′Ar′, Alk′X^(a)Ar′ or X^(a)R′ maybe prepared by coupling an intermediate of formula (3)

a) where L² is a group —X^(a)H with a reagent L³Alk′Ar′, or L³R′ whereL³ is a leaving group; or

b) where L² is a group —Alk′L³ with a reagent Ar′X^(a)H.

Leaving groups represented by L³ include halogen atoms such as iodine,chlorine or bromine atoms, sulphonyloxy groups such as arylsulpyhonyloxygroups, e.g. p-toluenesulphonyloxy or hydroxyl groups.

The coupling reaction may be carried out in the presence of a base, e.g.an inorganic base such as a carbonate, e.g. caesium or potassiumcarbonate, an alkoxide, e.g. potassium t-butoxide, or a hydride, e.g.sodium hydride, in a dipolar aprotic solvent such as an amide, e.g. asubstituted amide, such as dimethylformamide or an ether, e.g.diethylether or a cyclic ether such as tetrahydrofuran or halogenatedsolvents, such as dichloromethane. The temperature of the reactionmixture may vary from ambient temperature or above, e.g. around 40° C.to the reflux temperature. Where necessary, an activator may be used,such as diethyl-, diisopropyl-, or dimethylazodicarboxylate, in thepresence of a phosphine, such as triphenylphosphine and a base, such asan amine, e.g. triethylamine.

Intermediates of formula (3) where L² is a group —Alk′L³ wherein L³ is ahalogen atom may be prepared by reaction of an intermediate of formula(3) wherein Alk′L³ is a —Alk′OH group with a halogenating agent, such asan inorganic acid halide e.g. thienylchloride, or an anhydride such asan arylsulphonic anhydride, e.g. p.toluenesulphonic anhydride, usingconventional procedures.

Intermediates of formula (3) where L² is a group —X^(a)H may be preparedby deprotection of a protected compound of formula (4)

where P is a hydroxy, thio, or amino protecting group. Examples ofhydroxy protecting groups include, for example ether groups, such as acyclopentyloxy group. The deprotection reaction may take place in anaqueous solvent, such as an aqueous ether, e.g. dioxane-water, in thepresence of an acid, e.g. sulphuric acid at an elevated temperature.e.g. around 90° C. Another example of protecting group P includet-butyldimethylsilyloxy group which can be cleaved by treatment withtetrabutylammonium fluoride to regenerate the free hydroxy group.

Intermediates of formula (3) where Z is a group (A) in which R³ is ahydroxyl group and R⁷ is a hydrogen atom may be prepared by reacting aketone of formula (5)

with an organometallic reagent R⁵R⁶CHM, where M is a metal atom.

Metal atoms represented by Z include, for example, a lithium atom.

The reaction may be performed in a solvent such as an ether, e.g. acyclic ether such as tetrahydrofuran, at a low temperature e.g. around−70° C. to ambient temperature. This reaction is particularly suitablefor the preparation of compounds of formula (3) wherein R⁵ is anelectron deficient group such as a 2- or 4-pyridyl group.

Reagents R⁵R⁶CHM are either known compounds or may be prepared,preferably in situ during the above process, by reaction of a compoundAlkCH₂M [where Alk is an alkyl group such as n-propyl] with a compoundR⁵R⁶CH₂ where necessary in the presence of a base such as an amine e.g.diisopropylamine using the above-mentioned conditions.

Intermediates of formula (5) where L² is a group —X^(a)H in which—X^(a)— is —NH— and R⁴ is a hydrogen atom may be prepared from the knowncompound of formula (6)

by reduction with a reducing agent, such as a lithium aluminium hydride,to give the alcohol derivative. This in turn may be oxidised, forexample with manganese dioxide to afford an aldehyde of formula (5).

Intermediates of formula (3) where Z is a group (A) in which R³ is ahydroxyl group may be prepared by reacting a ketone of formula (5) witha reagent R⁵CHR⁶R⁷ using a base, such as an organometallic base, forexample an organolithium reagent e.g. n-butyllithium, in a solvent, suchas an ether, e.g. tetrahydrofuran, at around −70° C. to roomtemperature.

Ketones of formula (5) may be prepared by oxidation of an alcohol offormula (7)

using an oxidising agent, such as manganese (IV) oxide, in a solvent,such as dichloromethane, at room temperature.

Alternatively, ketones of formula (5) may be prepared by reaction of ahalide of formula (8)

[where Hal is a halogen atom such as a bromine or chlorine atom] byhalogen-metal exchange with a base such as n-butyllithium followed byreaction with a nitrile R⁴CN, an acid chloride R⁴COCl or an ester R⁴CO₂A(where A is an alkyl group, e.g. a methyl group), in a solvent such astetrahydrofuran at a low temperature, e.g. around −70° C., andsubsequent treatment with an acid such as hydrochloric acid at e.g. −20°C. to ambient temperature.

Alcohols of formula (7) may be prepared

(1) by reacting a halide of formula (8) e.g. a bromide, with an aldehydeR⁴CHO, in the presence of a base, such as n-butyllithium, in a solvent,e.g. tetrahydrofuran, at a temperature from around −70° C. to roomtemperature; or

(2) by reacting an aldehyde of formula (9) where W^(a) is a —CHO group(as described hereinbelow) with an organometallic compound, such as anorganolithium R⁴Li, or a Grignard R⁴MgBr, in a solvent, such astetrahydrofuran, at a low temperature, e.g. around −55° C. to 0° C.

Intermediates of formula (3) where Z is a group (B) may be prepared bycondensing an intermediate of formula (9)

where

(a) W^(a) is a —C(O)R⁴ group wherein R⁴ is as defined for formula (1)but is not a —CN or —CH₂CN group, with a compound R⁵CH₂R⁶; or where

(b) W^(a) is a —CH₂R⁴ group with an aldehyde or ketone R⁵COR⁶ where R⁵is as just defined for R⁴; or where

(c) W^(a) is a —C(O)R⁴ group with a silane derivative(Alk^(a))₃SiCH(R⁵)(R⁶), where Alk^(a) is an alkyl group; in eachinstance in the presence of a base or an acid in a suitable solvent.

Bases for use in these reactions include inorganic bases, for examplealkali and alkaline earth metal bases, e.g. hydroxides, such as sodiumor potassium hydroxide; alkoxides, for example sodium ethoxide; organicbases, for example amines such as piperidine; and organolithium bases,such as alkyllithium, e.g. n-butyllithium bases. Suitable solventsinclude alcohols such as ethanol, or ethers such as tetrahydrofuran.Acids for use in the reactions include organic acids, e.g. carboxylicacids such as acetic acid.

The reactions may be performed at any suitable temperature, for examplefrom around −78° C. to ambient temperature or to the reflux temperaturedepending on the nature of the starting materials.

In general, the base, acid, solvent and reaction conditions may beselected depending on the nature of the starting materials, from a rangeof known alternatives for reactions of this type.

In silane derivatives of formula (Alk^(a))₃SiCH(R⁵)(R⁶), Alk^(a) may befor example a C₁₋₆alkyl group such as a methyl group. Derivatives ofthis type may be prepared for example by reacting a compound R⁵—CH₂—R⁶with a silane derivative, such as a chlorotrialkylsilane, e.g.chlorotrimethylsilane in the presence of a base, e.g. lithiumdiisopropylamide, in a solvent, e.g. tetrahydrofuran, at a lowtemperature, e.g. around −10° C.

The starting materials R⁵COR⁶ and R⁵CH₂R⁶ are either known compounds ormay be prepared from known starting materials by methods analogous tothose used for the preparation of the known compounds.

Intermediates of formula (9) where —W^(a) is a —C(O)R⁴ group where R⁴ isan alkyl or aryl group (CH₂)_(t)Ar group, may be prepared by reacting analdehyde of formula (9) where —W^(a) is a —CHO group with anorganometallic reagent in a solvent, e.g. tetrahydrofuran, at lowtemperature, e.g. around 10° C., followed by oxidation with an oxidisingagent, such as manganese dioxide, in a solvent, e.g. dichloromethane.

Intermediates of formula (9) where —W^(a) is —CHO may be prepared byreacting a compound of formula (8) described above with anorganometallic reagent, such as n-butyllithium, in a solvent, such as anamide, e.g. dimethylformamide, at a low temperature, e.g. below −60° C.

Intermediates of formula (8) may be prepared by deprotecting a compoundof formula (10)

using reagents and conditions described herein for the obtention of anintermediate of formula (3) from an intermediate of formula (4) where L²is a group X^(a)H.

Intermediates of formula (10) may be prepared by protecting a compoundof formula (11)

Examples of protecting groups include hydroxy, thio or amino protectinggroups using conventional procedures [see Green, T. W. ibid]. Thus forexample, where X^(a) is an oxygen atom, the hydroxyl group may beprotected as an ether group, using a reagent Alk^(b)L³, where Alk^(b) isan alkyl group and L³ is a leaving group. Alkyl groups represented byAlk^(b) include cycloalkyl groups, such as cyclopentyl group, andleaving groups L³ include halogen atoms such as iodine, chlorine orbromine atoms or sulphonyloxy groups such as arylsulphonyloxy groups,e.g. p.toluenesulphonyloxy groups.

The reaction may be carried out in the presence of a base, e.g. aninorganic base such as a carbonate, e.g. caesium or potassium carbonate,an alkoxide, e.g. potassium-t-butoxide, or a hydride, e.g. sodiumhydride, in a dipolar aprotic solvent such as an amide, e.g. asubstituted amide such as dimethylformamide or an ether, e.g. a cyclicether such as tetrahydrofuran, at ambient temperature or above. e.g.around 40° C. to 50° C.

Halides of formula (11) where X^(a) is —O— may be prepared by oxydationof an aldehyde of formula (17) (where R is a hydrogen atom) as describedbelow using an oxidising agent such as 3-chloroperoxybenzoic acid in ahalogenated hydrocarbon such as chloroform at a temperature from around0° C. to room temperature.

Halides of formula (11) where X^(a) is —S— or —N(R^(b))— are eitherknown compounds or may be prepared from known starting materials bymethods analogous to those used for the preparation of the knowncompounds.

Compounds of formula (1) where Z is a group (A) in which R³ is ahydroxyl group and R⁷ is as described for compounds of formula (1) maybe prepared by reacting a compound or formula (11) with a reagentR⁵R⁶CHM or R⁵CHR⁶R⁷ using the conditions described hereinabove for theobtention of an intermediate of formula (3) from a ketone of formula(5).

In another process according to the invention, compounds of formula (1)where Z is a group (B) and R⁴ is a hydrogen atom or an alkyl or—(CH₂)_(t)Ar group may be prepared by reacting a compound of formula(12)

with a phosphonate ester (R^(d)O)(OR^(e))P(O)CH(R⁵)(R⁶) [where R^(d) andR^(e), which may be the same or different is an alkyl, or aralkyl group]in the presence of a base in a suitable solvent.

Suitable bases include organometallic bases such as organolithium, e.g.n-butyllithium, alkoxides, for example alkali metal alkoxides such assodium ethoxide or sodium methoxide and a hydride such as potassiumhydride or sodium hydride. Solvents include ethers, e.g. diethylether orcyclic ethers such as tetrahydrofuran and alcohol, e.g. methanol orethanol.

The phosphonate derivatives used in this reaction are either knowncompounds or may be prepared by reacting a phosphite P(OR^(d))₂(OR^(e))with a compound R⁵CHR⁶Hal [where Hal is a halogen atom, for example abromine atom] using conventional methods.

Intermediates of formula (12) where R⁴ is a hydrogen atom may beprepared by reacting a halide of formula (13)

where Hal is a halogen atom, e.g. a bromine or chlorine atom with anorganometallic reagent using the same reagents and conditions describedabove for the preparation of intermediates of formula (9) where W^(a) is—CHO from intermediates of formula (8).

Intermediates of formula (2) where ═W— is ═N— and R⁴ is H may beprepared from an acid of formula (14)

using the conditions described above for the preparation of anintermediate of formula (5) from an acid of formula (6).

Intermediates of formula (14) where L is X^(a)Alk′Ar or X^(a)R′ and—X^(a) is —O—, —S— or —NH—, may be prepared by reacting a halide offormula (15)

where Hal is a halogen atom, e.g. a bromine, chlorine or iodine atomwith a compound ArAlk′X^(a)H, where —X^(a)— is —O—, —S— or —NH— in thepresence of a base.

Bases used in this reaction include a hydride, such as sodium hydride,or an organometallic base such as butyllithium in a solvent, such as anamide, for example dimethylformamide at a temperature from roomtemperature to above, e.g. 80° C.

Intermediates of formula (15) may be prepared by reacting the knownamine of formula (16)

with nitrous acid (made in situ by reacting sodium nitrite with an acid,for example sulphuric acid or hydrobromic acid) to produce the diazoniumsalt. This in turn may be reacted with a haloacid, e.g. hydrobromic,hydrochloride or hydriodic acid if necessary in the presence of thecorresponding copper (I), halide (CuBr or Cul) or halogen Br₂, Cl₂ orI₂.

Intermediates of formula (13) where L is a —C(R)═C(R¹)(R²) group may beprepared by coupling a compound of formula (17)

where Hal is a halogen atom, e.g. a bromine atom with a phosphonium salt(R¹)(R²)CHP(D)₃Hal as described below for the preparation of compoundsof formula (1) from intermediates of formula (19).

Intermediates of formula (12) where R⁴ is an alkyl or —(CH₂)_(t)Ar groupmay be prepared by reaction of the corresponding compound of formula(12) where R⁴ is a hydrogen atom with an organometallic reagent,followed by oxidation, as described previously for the preparation ofintermediates of formula (9) where W^(a) is —C(O)R⁴ where R⁴ is an alkylor aryl group (CH₂)_(t)Ar from intermediates of formula (9) where R⁴ isa hydrogen atom.

In another process for the preparation of compounds of formula (1) whereZ is the group (B), an intermediate of formula (18)

may be coupled in a Heck reaction with an organopalladium compoundderived from a compound R⁵Hal [where Hal is a halogen atom such as abromine atom] and a palladium salt such as palladium acetate in thepresence of a phosphine such as tri-o-tolylphosphine and a base such astriethylamine at an elevated temperature and pressure.

Intermediate alkenes of formula (18) may be obtained by reaction of acorresponding intermediate of formula (12) using a Wittig reactionemploying a phosphonium salt such as methyltriphenylphosphonium bromidein the presence of a base such as n-butylithium and an inert solventsuch as tetrahydrofuran at, for example, 0° C. to ambient temperature.

Intermediates of formula (3) where L² is a —Alk′L³ group in which Alk′is an alkenylene chain —C═C—Alk′— and L³ is a hydroxyl group may beprepared by coupling a compound of formula (19)

where R is a hydrogen atom or an alkyl group such as a methyl group,with an olefination agent.

Particular examples of olefination agents include phosphonium salts suchas compounds HOAlk′P(D)₃Hal [where the hydroxyl group may need to beprotected using conventional protecting group] where Hal is a halogenatom, such as a bromine atom and D is an optionally substituted alkyl,e.g. methyl, or aryl, especially phenyl group; phosphoranesHOAlk′C═P(D)₃; phosphonates (DO)₂P(O)Alk′OH; or silane derivatives, forexample compounds of formula (D)₃SiAlk′OH e.g. trialkylsilanes such as(CH₃)₃SiAlk′OH.

Intermediates of formula (19) where R is an alkyl group, may be preparedby reacting an intermediate of formula (19) where R is a hydrogen atomwith an organometallic reagent, such as an alkyllithium or anorganomagnesium RMgHal, using the conditions described above, followedby oxidation of the resulting alcohol, using an oxidising agent, e.g.manganese dioxide.

Intermediates of formula (19) where R is a hydrogen atom may be preparedby deprotecting a protected aldehyde of formula (20)

where P¹ is a protected aldehyde group, e.g. a dioxanyl group, usingacid hydrolysis e.g. by reaction with trifluoroacetic acid or p-toluenesulphonic acid, in the presence of a solvent, e.g. acetone, or a mixtureof solvents, e.g. chloroform and water.

Intermediates of formula (20) may be prepared by protecting an aldehydeor ketone of formula (19) with an aldehyde or ketone protecting group,using for example a suitable diol, e.g. 1,3-propanediol, in the presenceof an acid catalyst, e.g. 4-toluene sulphonic acid, in a solvent, suchas an aromatic solvent, e.g. toluene, at an elevated temperature.

In general, this reaction may be used when it is desired to protect analdehyde in any intermediate described herein.

Compounds of formula (1) where L is a group —C(R)═C(R¹)(R²) or Alk′Ar′where Alk′ is an alkenylene chain —C═C—Alk′ may be prepared from anintermediate of formula (19) using an appropriate olefination agent.

Particular examples of olefination agents include phosphonium salts suchas compounds (R¹)(R²)CHP(D)₃Hal or Ar′Alk′P(D)₃Hal where Hal is ahalogen atom, such as a bromine atom, and D is an optionally substitutedalkyl, e.g. methyl, or aryl, especially phenyl, group; phosphoranes(R¹)(R²)C═P(D)₃ or Ar′Alk′═P(D)₃; phosphonates (DO)₂P(O)CH(R¹)(R²) or(DO₂)P(O)Alk′Ar′; or silane derivatives, for example compounds offormula (D₃)SiC(R¹)(R²) or (D₃)SiAlk′Ar′, e.g. trialkylsilanes such as(CH₃)₃SiC(R¹)(R²) or (CH₃)₃SiAlk′Ar′.

Bases for use in the above reaction include organometallic bases, forexample, an organolithium compound such as an alkyllithium e.g.n-butyllithium, a hydride, such as sodium or potassium hydride or analkoxide, such as a sodium alkoxide, e.g. sodium methoxide.

The reaction may be performed in a suitable solvent, for example a polaraprotic solvent, such as an alkyl sulphoxide, e.g. methyl sulphoxide, anamide such as N,N-dimethylformamide or hexamethylphosphorous triamide; anon-polar solvent, such as an ether, e.g. tetrahydrofuran or diethylether or an aromatic solvent such as benzene, toluene or xylene; or apolar protic solvent, such as an alcohol, for example ethanol.Preferably the reaction is carried out at a low temperature, for examplefrom around −78° C. to around room temperature.

The olefination agents used in this reaction are either known compoundsor may be prepared from known starting materials using reagents andconditions similar to those used to prepare the known compounds. Forexample, a phosphorane may be prepared in situ by reaction of aphosphonium salt with a base of the type described above. In anotherexample, a phosphonate reagent may be prepared by reacting a halideAlk′Hal with a phosphite (DO)₃P, as described in the Arbuzov reaction.Silane derivatives may be prepared by reaction of a halosilane (D)₃SiHalwhere Hal is a halogen atom, for example a chlorine atom, with a base,such as lithium diisopropylamide, in a solvent, such as an ether, forexample a cyclic ether, e.g. tetrahydrofuran, at low temperature, e.g.−10° C.

According to a further aspect of the invention, compounds of formula (1)where L is a group —C(R)═CH(R¹) and R¹ is an optionally substitutedalkyl, alkenyl or alkenyl group may also be prepared by reaction of anintermediate of formula (19) with an organometallic reagent, followed bydehydration of the corresponding alcohol.

Examples of organometallic reagents include organolithium R¹Li ororganomagnesium R¹MgHal reagents. The reaction with the organometallicreagent may be performed in a solvent such as an ether, e.g. diethylether or for example a cyclic ether such as tetrahydrofuran, at a lowtemperature for example −10° C. to room temperature. The dehydration maybe performed using an acid, for example an organic acid such asp.toluene sulphonic acid or trifluoracetic acid, in the presence of abase, such as an amine, e.g. triethylamine.

In yet another process according to the invention, compounds of formula(1) wherein R³, R⁶ and R⁷ is each a hydrogen atom may be prepared bydecarboxylation of an acid of formula (21):

The reaction may be carried out by treatment of the compound of formula(21) with a base, for example an inorganic base such as a hydroxide,e.g. sodium hydroxide in a solvent such as an alcohol, e.g. ethanol, atan elevated temperature e.g. the reflux temperature, followed byacidification of the reaction mixture to a pH of around pH4 to aroundpH6 using an acid such as an inorganic acid, e.g. hydrochloric acid, atan elevated temperature, e.g. the reflux temperature.

If desired, the acid of formula (21) may be generated in situ from thecorresponding ester or nitrile using the above reaction conditions, orby initial treatment with an acid.

Intermediates of formula (21) may be prepared by reacting a compound offormula (22)

[where R¹⁵ is an ester of an acid —CO₂H (e.g. an alkyl ester such as anethyl ester) or a nitrile —CN], with a Grignard reagent R⁴MgBr, in thepresence of a complexing agent, e.g. a copper (I) bromide-dimethylsulphide complex, or a copper (I) chloride, or with an organolithiumcompound, e.g. R⁴Li, in a solvent, e.g. tetrahydrofuran, at lowtemperature, e.g. around −40° C., followed by treatment with a base oran acid to yield the acid of formula (21). The Grignard and the lithiumreagents are either known compounds or may be prepared in a mannersimilar to that used to synthesise the known compounds.

Compounds of formula (22) may be obtained by reacting an adehyde offormula (12) with an ester or nitrile R⁵CH₂R¹⁵ in an acid solvent, suchas acetic acid, at an elevated temperature, for example the refluxtemperature, in the presence of a base, such as ammonium acetate.

In a further process according to the invention a compound of formula(1) wherein R³, R⁶ and R⁷ is each a hydrogen atom and R⁵ is a heteroarylgroup may be generally prepared by cyclisation of a compound of formula(23):

where R¹⁶ is a carboxylic acid [—CO₂H] group or a reactive derivativethereof; or a nitrile [—CN] or an imine salt with a bifunctional reagentW¹R^(5a)W₂ and, where necessary, a compound R^(5b)W³ [where W¹, W² andW³, which may be the same or different, is each a reactive functionalgroup or a protected derivative thereof; and R^(5a) and R^(5b) arecomponents of the heteroaryl group R⁵ such that when added together withW¹, W² and W³ to the group R¹⁶ in compounds of formula (23) theresulting group —RW¹R^(5a)W² or —RW¹R^(5a)W²R^(5b)W³ constitutes theheteroaryl group R⁵].

Reactive derivatives of carboxylic acids for use in this reactioninclude acid halides, (e.g. acid chlorides), amides, includingthioamides, or esters, including thioesters. Imine salts include forexample salts of formula [e.g. —C(OAlk)═NH₂ ⁺A⁻, where Alk is aC₁₋₄alkyl group and A⁻ is a counterion e.g. a chloride ion].

In this general reaction the reactive functional groups represented byW¹, W² or W³ may be any suitable carbon, nitrogen, sulphur or oxygennucleophiles. Particular examples include simple nucleophiles such ascarbanions [e.g. generated by the coupling of an alkyl group with anorganometallic compound], amino, thiol and hydroxyl groups.

In general, the cyclisation reaction will initially be performed in asolvent, for example an inert solvent such as a halocarbon, e.g.dichloromethane, an ether, e.g. a cyclic ether such as tetrahydrofuran,or a hydrocarbon, e.g. an aromatic hydrocarbon such as toluene, from alow temperature, e.g. around −70° C., to around the reflux temperature,where necessary in the presence of a base or a thiation reagent, e.g.Lawesson's reagent, followed if necessary by heating, to an elevatedtemperature, e.g. the reflux temperature.

Thus, in one particular example, compounds of formula (1) wherein R³, R⁶and R⁷ is each a hydrogen atom and R⁵ is a benzothiazolyl, benzoxazolylor benzimidazolyl group may be prepared by reaction of a compound offormula (19) where R¹⁶ is an acid halide, e.g. acid chloride, with areagent W¹R^(5a)W² which is 2-aminothiophenol, 2-hydroxyphenol, or1,2-diaminobenzene respectively in the presence of a base e.g. anorganic amine such as pyridine, in a solvent e.g. a halocarbon such asdichloromethane, from around −70° C. to the reflux temperature.

In another example of the general cyclisation process, a compound offormula (23) where R¹⁶ is an acid halide as described above may bereacted with a compound W¹R^(5a)W² which is a monoalkylmalonate, e.g.ethyl hydrogen malonate, followed by reaction with a compound R^(5b)W³which is hydrazine to give a compound of formula (1) wherein R³, R⁶ andR⁷ is each a hydrogen atom and R⁵ is a 5-hydroxypyrazolyl group.

In another variation of the cyclisation process, the halide of formula(23) may be reacted with a compound W¹R^(5a)W² which isBrMg(CH₂)₃[—O(CH₂)₂O—] followed by reaction in an acid solution with acompound R^(5b)W³ which is methylamine to yield a compound of formula(1) wherein R³, R⁶ and R⁷ is each a hydrogen atom and R⁵ is a N-methylpyrrole group.

In a further example of the cyclisation process, the acid halide offormula (23) may be reacted with a compound W¹R^(5a)W² which isH₂NNHCSNH₂ in an aromatic hydrocarbon such as toluene, at an elevatedtemperature, e.g. around 150° C., followed by treatment with a base,e.g. an inorganic base such as sodium bicarbonate to give a compound offormula (1) wherein R³, R⁶ and R⁷ is each a hydrogen atom and R⁵ is a1,2,4-triazolyl-5-thiolate group.

Intermediate compounds of formula (23) are particularly useful and forma further aspect of the invention. Active derivatives of the acids offormula (23) and other compounds of formula (23) where R¹⁶ is a nitrileor an imine salt may be prepared from the corresponding acids [where R¹⁶is —CO₂H] using conventional procedures for converting carboxylic acidsto such compounds, for example as described in the Examples hereinafter.

Acids of formula (23) [where R¹⁶ is —CO₂H] may be prepared byhydrolysing a diester of formula (24)

where A¹ is a C₁₋₄alkyl group, e.g. an ethyl group, with a base, e.g.sodium hydroxide, in a solvent, e.g. dioxane, at an elevatedtemperature, e.g. the reflux temperature, followed by acidification atan elevated temperature.

Diesters of formula (24) may be prepared by reacting a diester offormula (24)

with an organometallic reagent, such as a Grignard reagent using theconditions described above for the preparation of alcohols of formula(1).

In yet another process according to the invention, a compound of formula(1) where Z is a group (C) may be prepared by coupling a compound offormula (25),

where E is a boronic acid —B(OH)₂ or a tin reagent Sn(R)₃, in which R isan alkyl group, for example a methyl group, with a reagent Z—L⁴, whereL⁴ is a leaving group, in the presence of a complex metal catalyst.

Particular leaving groups L⁴ include for example halogen atoms, e.g.bromine, iodine or chlorine atoms and an alkyl sulphonate, such astrifluoromethanesulphonate.

Suitable catalysts include heavy metal catalysts, for example palladiumcatalysts, such as tetrakis (triphenylphosphine)palladium. The reactionmay be performed in an inert solvent, for example an aromatichydrocarbon such as toluene or benzene, or an ether, such asdimethoxyethane or dioxane, if necessary in the presence of a base, e.g.an alkali carbonate such as sodium carbonate, at an elevatedtemperature, e.g. the reflux temperature. In general, the metal catalystand reaction conditions may be selected, depending on the nature of thecompound of formula (25) and/or the compound Z—L⁴ from a range of knownalternatives for reactions of this type [see for example Miyaura, N etal, Synth. Comm. (1981), 11, 513; Thompson, W. J. and Gaudino, J., J.Org. Chem, (1984), 49, 5237 and Sharp, M. J. et al, Tetrahedron Lett.(1987), 28, 5093].

Intermediates Z—L⁴ are either known compounds or may be prepared fromknown starting materials by methods analogous to those used for thepreparation of the known compounds. Thus, for example, where it isdesired to obtain a compound Z—L⁴ where L⁴ is a halogen atom such asbromine or chlorine atom and this compound is not readily available,such a compound may be prepared by (1) treatment of the correspondingamine with t-butyl nitrite and anhydrous CuCl₂ or CuBr₂ at elevatedtemperature, or (2) with t-butyl thionitrite or t-butyl thionitrate andCuCl₂ or CuBr₂ at room temperature followed by reaction with anappropriate copper (I) halide such as cuprous chloride or bromide in anaqueous acid.

Intermediates of formula (25) may be prepared by halogen-metal exchangebetween a compound of formula (13) where Hal is a bromine atom and anorganometallic agent such as n-butyl or t-butyllithium followed byreaction with a borate such as triisopropylborate or a tin reagent(R)₃SnX, where R is as described above and X is a halogen atom, such aschlorine atom, optionally at a low temperature e.g. around −70° C., in asolvent such as tetrahydrofuran.

According to another aspect of the invention, a compound of formula (1)where Z is a group (D) in which —Z¹ is —NR¹²C(O)— or —C(O)NR¹²— may beprepared by coupling a compound of formula (26)

where —A is a —CO₂H or —NHR¹² group,

or an active derivative thereof with a compound R¹²NH(Alk)_(t)(X)_(n)Aror Ar(X)_(n)(Alk)_(t)CO₂H or an active derivative thereof. Activederivatives of acids of formula (26) or Ar(X)_(n)(Alk)_(t)CO₂H include,for example, acid anhydrides, or acid halides, such as acid chlorides.

The coupling reaction may be performed using standard conditions forreactions of this type. Thus for example, the reaction may be carriedout in a solvent, for example an inert organic solvent such as an ether,e.g. a cyclic ether such as tetrahydrofuran, an amide, e.g. asubstituted amide such as dimethylformamide, or a halogenatedhydrocarbon such as dichloromethane, at a low temperature, e.g. −30° C.to ambient temperature such as −20° C. to 0° C., optionally in thepresence of a base, e.g. an organic base such as an amine, e.g.triethylamine or a cyclic amine such as N-methylmorpholine. Where anacid of formula (17) or Ar(X)_(n)(Alk)_(t)CO₂H is used, the reaction mayadditionally be performed in the presence of a condensing agent, forexample a diimide such as N,N′-dicyclohexylcarbodiimide, advantageouslyin the presence of a triazole such as 1-hydroxybenzotriazole.Alternatively, the acid may be reacted with a chloroformate, for exampleethylchloroformate, prior to reaction with the amine.

Intermediate acids of formula (26) where A is a —CO₂H group may beprepared by hydrolysis of a corresponding ester of formula (27)

where Alk^(a) is an alkyl group;

by heating in the presence of a base, for example an alkali metalhydroxide such as lithium hydroxide in a solvent such as an alcohol,e.g. methanol.

Intermediates of formula (26) where A is a —NHR¹² group and R¹² is ahydrogen atom, may be prepared by hydrogenation of a corresponding nitrocompound of formula (28)

using the reagents described below for the hydrogenation of a compoundof formula (1) where —L is a —CH═C(R¹)(R²) chain to a compound offormula (1) where —L is a —CH₂CH(R¹)(R²) chain.

Intermediates of formula (26) where A is a NHR¹² group in which R¹² isan alkyl group may be prepared by alkylation of an intermediate offormula (26) in which R¹² is a hydrogen atom, using an alkyl halide e.g.an alkyl iodide in a solvent, such as an aromatic solvent, for examplebenzene.

Intermediates of formulae (27) and (28) and the reagentsR¹²NH(Alk)_(t)(X)_(n)Ar and Ar(X)_(n)(Alk)_(t)CO₂H are known compoundsor may be prepared from known starting materials by methods analogous tothose used for the preparation of the known compounds.

In yet another aspect of the invention compounds of formula (1) where Zis a group(D) in which Z¹ is a —C≡C— chain and n and t is each zero maybe prepared by reacting a compound of formula (29)

with a reagent Ar(X)_(n)(Alk)_(t)L⁵ (where L⁵ is a leaving group) in thepresence of a metal complex catalyst, and in a solvent

Examples of L⁵ leaving groups include halogen atoms such as bromine,iodine or chlorine atoms or alkyl triflate such as trifluoromethanesulphonate. Suitable solvents include for example an amine, for examplea tertiary amine, e.g. triethylamine, a secondary amine, e.g.dimethylamine or a primary amine e.g. n-butylamine.

Metal complex catalysts include palladium catalysts, such asPd(Hal)₂(PPh₃)₂ or Pd(PPh₃)₄ (where Hal is a halogen atom e.g. achlorine atom) in the presence of copper (I) iodide, at a temperaturefrom room temperature to an elevated temperature, e.g. the refluxtemperature. (Comprehensive organic synthesis, vol. 3., 531-541; Trost,Fleming. Pergamon Press, 1991).

Intermediates of formula (29) may be prepared by reacting a dihalide offormula (30)

where Hal is a halogen atom, e.g. a bromine atom, with a base such as anorganometallic base, for example an organolithium, e.g. n-butyllithium,in a solvent such as an ether, e.g. tetrahydrofuran or diethylether, ata temperature from around −78° C. to room temperature.

Intermediates of formula (30) may be prepared by reacting an aldehyde offormula (12) (where R⁴ is a hydrogen atom) with a reagent Hal₂C═P(Ar¹)₃(where Hal is a halogen atom, such as a bromine atom and Ar¹ is an arylgroup, such as phenyl or o-tolyl), prepared in situ from C(Hal)₄ andP(Ar¹)₃ in the presence of a base, such a an organometallic base, forexample an organolithium, e.g. n-butyllithium).

In a futher aspect of the invention, compounds of formula (1) where Z isa group (D) in which Z¹ is a —NR¹²SO₂— or —SO₂NR¹²— group may beprepared by reaction of a compound of formula (30)

where (a) W^(b) is a —NHR¹² group with a compoundAr(X)_(n)(Alk)_(t)SO₂Hal [where Hal is a halogen atom, e.g. a bromine orchlorine atom], if necessary in the presence of a base; or,

(b) W^(b) is a —SO₂Hal group with a compound Ar(X)_(n)(Alk)_(t)NHR¹²using the reagents and conditions described in (a) above.

Examples of bases used in this reaction include amine, such as tertiaryamine, for example triethylamine, in a solvent such as an ether, forexample a cyclic ether, e.g. tetrahydrofuran. Compounds Ar(X)_(n)(Alk)_(t)NHR¹² and compounds of formula (30) where W^(b) is a—NHR¹² group are known compounds or may be prepared using similarreagents and conditions to those used to prepare the known compounds.

Compounds of formula (30) where W^(b) is —SO₂Hal, may be prepared byreacting an intermediate halide of formula (13) with an organometallicreagent, such as an organolithium, e.g. n-butyllithium in a solvent,such as an ether, e.g. tetrahydrofuran, at a low temperature e.g. around−60° C. to −100° C. followed by reaction with sulphuryl chloride, in asolvent, such as an aliphatic solvent, e.g. n-hexane, at a lowtemperature, e.g. around 0° C.

Compounds of formula (1) where L is a group —CH(R¹)(R²) where R² is a—CO₂H group may be prepared by reacting a compound of formula (31)

where Hal¹ is a halogen atom, such as a chlorine or a bromine atom, witha diazoalkane CH(R¹)N₂ to give the corresponding diazoketone derivativewhich is then treated with water and silver oxide or with silverbenzoate and triethylamine.

Intermediates of formula (31) may be prepared by oxidation of analdehyde of formula (19), using an oxidising agent, such as permanganateor chromic acid, to give the corresponding carboxylic acid which is thenreacted with a halide reagent, such as thionylchloride, phosphorouspentachloride or phosphorous pentabromide.

Compounds of formula (1) may also be prepared by interconverting othercompounds of formula (1). Thus, for example where Z is a group (A) inwhich R³ is a hydrogen atom may be prepared by hydrogenation of acompound of formula (1) where Z is a group (B).

The hydrogenation may be performed using for example hydrogen in thepresence of a catalyst. Suitable catalysts include metals such asplatinum or palladium optionally supported on an inert carrier such ascarbon or calcium carbonate; nickel, e.g. Raney nickel, or rhodium. Thereaction may be performed in a suitable solvent, for example an alcoholsuch as methanol or ethanol, an ether such as tetrahydrofuran ordioxane, or an ester such as ethyl acetate, optionally in the presenceof a base, for example a tertiary organic base such as triethylamine, atfor example ambient temperature.

Alternatively, the reaction may be accomplished by transferhydrogenation using an organic hydrogen donor and a transfer agent.Suitable hydrogen donors include for example acids, such as formic acid,formates, e.g. ammonium formate, alcohols, such as benzyl alcohol orethylene glycol, hydrazine, and cycloalkenes such as cyclohexene orcyclohexadiene. The transfer agent may be for example a transitionmetal, for example palladium or platinum, optionally supported on aninert carrier as discussed above, nickel, e.g. Raney nickel, ruthenium,e.g. tris (triphenylphosphine) ruthenium chloride or copper. Thereaction may generally be performed at an ambient or elevatedtemperature, optionally in the presence of a solvent, for example analcohol such as ethanol or an acid such as acetic acid.

In a second example of an interconversion process, compounds of formula(1) where Z is a group (A) in which R⁷ is an OR^(c) group where R^(c) isan alkyl or alkenyl group, may be prepared by reacting a compound offormula (1) where Z is a group (A) in which R⁷ is a —OH group, with areagent R^(c)—OH, in the presence of an acid, such as sulphuric acid.

In another example of an interconversion process, compounds of formula(1) where Z is a group (A) in which R⁷ is an OR^(c) group where R^(c) isa carboxamido or thiocarboxamido group may be prepared by reaction of acompound of formula (1) where Z is a group (A) in which R⁷ is a —OHgroup, with an isocyanate R^(c)N═C═O or an isothiocyanate R^(c)N═C═S inthe presence of a base, such as sodium hydride, in a solvent, such astetrahydrofuran. Compounds R^(c)N═C═O and R^(c)N═C═S are known compoundsor may be prepared using the reagents and conditions used for thepreparation of the known compounds. When R^(c)N═C═S is not available, acompound of formula (1) where R^(c) is a thiocarboxamido group may beprepared by interconverting a compound of formula (1) where R^(c) is acarboxamido group using a thiation reagent, such as Lawesson's reagent[2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-di-sulphide],in an aromatic solvent, such as xylene or toluene.

In a yet another example of an interconversion process, a compound offormula (1) where Z is a group (A) in which R³ is a fluorine atom may beprepared by reacting a compound of formula (1) where Z is a group (A) inwhich R³ is a hydroxyl group, with a fluorinating reagent, such asdiethylaminosulphur trifluoride (DAST), in a solvent, for example achlorinated solvent, e.g. dichloromethane, at a low temperature, e.g.around 0° C.

In a still further example of an interconversion process, a compound offormula (1) where Z is a group (A) in which R³ is an alkyl group, may beprepared by alkylation of a compound of formula (1) where Z is a group(A), and R³ is a hydrogen atom, with a reagent R³L³ using a base, forexample n-butyllithium or lithium diisopropylamide. In this process, R⁴in the starting material is preferably an electron withdrawing group.

In a still further example of interconversion process, a compound offormula (1) where L is (X^(a))_(n)Alk′Ar′ or Alk′X^(a)Ar′ where Alk′ isan alkylene chain, may be prepared by hydrogenation of a compound offormula (1) where Alk′ is an alkenylene or alkynylene chain, using forexample hydrogen in the presence of a metal catalyst, as described abovefor the hydrogenation of a compound of formula (1) where Z is a group(B) to give a compound of formula (1) where Z is the group A.

Compounds of formula (1) where Z is the group (B) may also be preparedby dehydrating a compound of formula (1) where Z is the group (A) and R³is a hydroxyl group, by using an acid, e.g. trifluoroacetic acid, in thepresence of a base, such as an amine, e.g. triethylamine, in a solvent,such as dichloromethane, at a low temperature, e.g. around −10° C.

Where it is desired to obtain a particular enantiomer of a compound offormula (1) this may be produced from a corresponding mixture ofenantiomers using any suitable conventional procedure for resolvingenantiomers.

Thus for example diastereomeric derivatives, e.g. salts, may be producedby reaction of a mixture of enantiomers of formula (1) e.g. a racemate,and an appropriate chiral compound, e.g. a chiral acid or base. Suitablechiral acids include, for example, tartaric acid and other tartratessuch as dibenzoyl tartrates and ditoluoyl tartrates, sulphonates such ascamphor sulphonates, mandelic acid and other mandelates and phosphatessuch as 1,1′-binaphthalene-2,2-diyl hydrogen phosphate. Thediastereomers may then be separated by any convenient means, for exampleby crystallisation and the desired enantiomer recovered, e.g. bytreatment with an acid or base in the instance where the diastereomer isa salt.

In another resolution process a racemate of formula (1) may be separatedusing chiral High Performance Liquid Chromatography. Alternatively, ifdesired a particular enantiomer may be obtained by using an appropriatechiral intermediate in one of the processes described above.

N-oxides of compounds of formula (1) may be prepared for example byoxidation of the corresponding nitrogen base using an oxidising agentsuch as hydrogen peroxide in the presence of an acid such as aceticacid, at an elevated temperature, for example around 70° C. to 80° C.,or alternatively by reaction with a peracid such as peracetic acid in asolvent, e.g. dichloromethane, at ambient temperature.

Salts of compounds of formula (1) may be prepared by reaction of acompound of formula (1) with an appropriate acid or base in a suitablesolvent or mixture of solvents e.g. an organic solvent such as an ethere.g. diethylether, or an alcohol, e.g. ethanol using conventionalprocedures.

The following Examples illustrate the invention. In the Examples, thefollowing abbreviations are used DME—ethylene glycol dimethyl ether;THF—tetrahydrofuran; CH₂Cl₂—dichloromethane; Et₂O—ether; EtOH—ethanol;RT—room temperature; DMF—N,N-dimethylformamide; EtOAc—ethyl acetate;MeOH—methanol.

Intermediates 1-6 were prepared as described in International PatentSpecification No. WO 94/14742.

INTERMEDIATE 1 3-Cyclopentyloxy-4-methoxybenzaldehyde INTERMEDIATE 2(3-Cyclopentyloxy-4-methoxyphenyl)phenylketone INTERMEDIATE 3(±)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-hydroxy-2-phenylethyl]pyridineINTERMEDIATE 4 (E) and (Z) isomers of4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethenyl]pyridineINTERMEDIATE 5(±)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridineINTERMEDIATE 6 (i)(+)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine (ii)(−)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-phenylethyl]pyridineINTERMEDIATE 7 a)(R)-4-[2-(3-Hydroxy-4-methoxyphenyl)-2-phenylethyl]pyridine

Intermediate 6 (i) (430 mg) in dioxane/water (20 ml:10 ml) containingconcentrated H₂SO₄ (10 ml) was heated at 90° C. for 1 h. The reactionmixture was cooled, neutralised with aqueous NaHCO₃ then concentrated invacuo. The residue was partitioned between EtOAc (25 ml) and H₂O (15ml), and the organic phase separated. The extract was washed with brine(25 ml), dried (MgSO₄) and concentrated in vacuo. The residue wasrecrystallised (EtOH) to afford the title compound (240 mg) as anoff-white crystalline solid m.p. 195-197° C. (Found: C, 78.66; H, 627;N, 4.59. C₂₀H₁₉NO₂ requires C, 78.64; H, 6.18; N, 4.42%); δH (CDCl₃)3.30 (2H, d, J 8 Hz, CHCH ₂), 3.86 (3H, s, OMe), 4.13 (1H, t, J 8 Hz,CHCH₂), 5.7 (1H, br s, OH), 6.63 (1H, dd, J 8.3 Hz, ArH para to OH),6.71 (1H, d, J 8.3 Hz, ArH ortho to OMe), 6.80 (1H, d, J 2.2 Hz, ArHortho to OH), 6.93 (2H, dd, J 4.5, 1.5 Hz, pyridine H ₃, H ₅), 7.1-7.3(5H, m, C₆H₅), and 8.37 (2H, dd, J 4.5, 1.5 Hz, pyridine H ₂,H ₆).

The following Intermediate was prepared in a manner similar toIntermediate 7a)

b) (E)-4-[2-(3-Hydroxy-4-methoxyphenyl)ethenyl]pyridine

From Intermediate 20 (8.0 g, 27.1 mmol) in toluene (200 ml) andp-toluenesulphonic acid H₂O (10.3 g, 54.2 mmol) under a nitrogenatmosphere. Recrystallisation (EtOH) gave the title compound (3.8 g) asan amorphous yellow solid. m.p. 196-199° C. (Found C, 73.73; H, 6.03; N,6.06. C₁₄H₁₃NO₂ requires C, 73.99; H, 5.77; N, 6.16%). δH (300 MHz;CDCl₃) 3.92 (3H, s, OCH ₃), 6.22 (1H, br s, OH), 6.86 (1H, d, H 8.3 Hz,ArH ₄), 6.86 (1H, d, J 16.2 Hz, HC═C (trans)), 7.01 (1H, dd, J 8.3, 2.1Hz, ArH ₆), 7.17-7.26 (2H, m, ArH ₂ and HC═C), 7.34 (2H, dd, J 4.6, 1.6Hz, pyridine H ₃, H ₅), and 8.55 (2H, t, J 4.6, 1.4 Hz, pyridine H ₂,H₆).

INTERMEDIATE 8 2-Methoxy-4-(3-pyridyl)benzaldehyde

A mixture of 5-bromo-2-methoxybenzaldehyde (10.00 g, 1.82 mmol) andtetrakis (triphenylphosphine)palladium (O) (2.10 g, 1.82 mmol, 3.9 mol%) in DME (filtered through Al₂O₃) (50 ml) was stirred at RT for 0.25 h.Sodium carbonate (2M, 50 ml, 0.10 mol %) and diethyl (3-pyridyl)borane(6.817 g, 46.36 mmol) were added, the mixture heated to reflux for 5.5 hthen allowed to stand at RT overnight. The dark brown reaction mixturewas partitioned between water (50 ml) and Et₂O (100 ml) and the organiclayer separated and combined with two further Et₂O extracts (1×50 ml,1×25 ml). The organic phase was extracted with 2N hydrochloric acid(2×50 ml) then the aqueous extract was basified with 3M NaOH andextracted with Et₂O (1×150 ml, 2×50 ml). The combined organic extractwas washed with brine (50 ml), dried (Na₂SO₄), concentrated in vacuothen submitted to column chromatography [SiO₂; Et₂O] to furnish thetitle compound (3.318 g) as a pale yellow solid (Found: C, 73.40; H,5.20; N, 6.44. C₁₃H₁₁NO₂ requires C, 73.23; H, 5.20; N, 6.57%.).

INTERMEDIATE 9 2-(5-Bromo-2-methoxyphenyl)-1,3-dioxane

A mixture of 5-bromo-2-methoxybenzaldehyde (52.3 g, 243 mmol),1,3-propanediol (30 ml, 31.6 g, 415 mmol), and 4-toluenesulphonic acid(0.3 g) in toluene (350 ml) was heated to reflux in a Dean-Starkapparatus for 20 h. The mixture was cooled to RT, washed with saturatedNaHCO₃ solution (100 ml), then the organic layer was separated andcombined with a CH₂Cl₂ solution (100 ml). The extract was washed (brine;50 ml), dried (Na₂SO₄), and concentrated in vacuo to give a brown oil(66.2 g). The crude product was distilled to afford the title compound(58.2 g) as a colourless viscous oil b.p. 115-120° C., 0.02 mmHg δH (80MHz; CDCl₃) 1.2-1.5 (1H, br m, CH₂CHHCH₂), 1.9-2.4 (1H, m, CH₂CHHCH₂),3.78 (3H, s, OMe), 3.6-4.4 (4H, m, CH ₂CH₂CH ₂), 5.76 (1H, s, OCH), 6.67(1H, d, J 8.8 Hz, ArH ortho to OMe), 7.33 (1H, dd, J 8.8, 2.3 Hz, ArHpara to acetal), and 7.68 (1H, d, J 2.3 Hz, ArH ortho to acetal); m/z(El) 274 (44%), 273 (31), 272 (45), 271 (27), 216 (34), 215 (47), 214(35), 213 (44), 193 (34), 135 (22), and 87 (100).

INTERMEDIATE 10 3-[2-(1,3-Dioxanyl)]-4-methoxybenzaldehyde

n-BuLi (1,6M solution in hexane) (125 ml, 200 mmol, 1.06 equiv.) wasadded dropwise to a solution of Intermediate 9 (51.65 g, 189 mmol) inTHF (250 ml) at below −65° C. After 3.5 h, DMF (20 ml, 258 mmol, 1.37equiv.) was added at below −60° C. The reaction mixture was allowed towarm to RT then poured into hydrochloric acid (0.05 M; 500 ml) andimmediately extracted with CH₂Cl₂ (500 ml, 2×150 ml). The extract waswashed (brine; 200 ml), dried (K₂CO₃), and concentrated in vacuo to givea pale yellow oil (44.0 g). The crude product was triturated with warmhexane (250 ml) to afford the title compound (38.75 g) as an off-whitecrystalline solid δH (80 MHz; CDCl₃) 1.3-1.6 (1H, br m, CH₂CHHCH₂),1.8-2.5 (1H, m, CH₂CHHCH₂), 3.89 (3H, s, OMe), 3.7-4.4 (4H, m, CH ₂CH₂CH₂), 5.82 (1H, s, OCH), 6.93 (1H, d, J 8.4 Hz, ArH ortho to OMe), 7.82(1H, dd, J 8.4, 2.2 Hz, ArH para to acetal), 8.12 (1H, d, J 2.2 Hz, ArHortho to acetal), and 9.84 (1H, s, CHO).

INTERMEDIATE 113-[3-(1,3-Dioxan-2-yl)-4-methoxyphenyl]-2-(4-pyridyl)propenenitrile

A mixture of Intermediate 10 (15.0 g, 67.5 mmol) and4-pyridylacetonitrile hydrochloride (10.75 g, 69.5 mmol) was stirred atRT in a mixture of EtOH (300 ml) and NaOH solution (3M; 40 ml, 150mmol). After 1 h, the precipitate was collected by filtration, washedwith EtOH (50 ml), then Et₂O (25 ml) and dried in vacuo to afford thetitle compound (15.85 g) as a very pale yellow solid δH (80 MHz; CDCl₃)1.3-1.7 (1H, br m, CH₂CHHCH₂), 2.0-2.4 (1H, m, CH₂CHHCH₂), 3.90 (3H, s,OMe), 3.8-4.4 (4H, m, CH ₂CH₂CH ₂), 5.83 (1H, s, OCH), 6.95 (1H, d, J8.5 Hz, ArH ortho to OMe), 7.47 (2H, dd, J 4.6, 1.7 Hz, pyridine H ₃, H₅), 7.63 (1H, s, CH═C), 7.96 (1H, d, J 2.4 Hz, ArH ortho to acetal),8.20 (1H, dd, J 8.5, 2.4 Hz, ArH para to acetal), and 8.61 (2H, dd, J4.6, 1.7 Hz, pyridine H ₂, H ₆).

INTERMEDIATE 12 5-Bromo-2-methoxybenzylidenecyclopentane

n-BuLi (1.6M solution in hexane) (72.5 ml, 116 mmol) was added dropwiseat 0° C. to a solution of cyclopentyltriphenylphosphonium bromide (45.8g, 111 mmol) in THF (300 ml). The red solution was stirred at 0° C. for0.5 h then treated with a solution of 5-bromo-2-methoxybenzaldehyde(23.5 g, 109 mmol) in THF (150 ml). The reaction mixture was stirred atRT overnight, concentrated in vacuo, then partitioned between CH₂Cl₂(250 ml) and water (150 ml). The organic phase was separated andcombined with further CH₂Cl₂ extracts (2×50 ml). The organic phase waswashed (brine; 50 ml), dried (Na₂SO₄), and concentrated in vacuo. Theresidue was subjected to chromatography (SiO₂; CH₂Cl₂) to afford thetitle compound (24.6 g), as a colourless oil δH (80 MHz; CDCl₃) 1.6-1.9(4H, br m, CH₂(CH ₂)₂), 2.3-2.6 (4H, br m, CH ₂(CH₂)₂CH ₂), 3.76 (3H, s,OMe), 6.4-6.5 (1H, br m, CH═C), 6.65 (1H, d, J 8.5 Hz, ArH ortho toOMe), 7.18 (1H, dd, J 8.5, 2.4 Hz, ArH para to olefin), and 7.39 (1H, d,J 2.4 Hz, ArH ortho to olefin).

INTERMEDIATE 13 5-Formyl-2-methoxybenzylidenecyclopentane

n-BuLi (1.6M solution in hexane) (22 ml, 27.7 mmol, 1.1 equiv) was addeddropwise at below −70° C. to a solution of Intermediate 12 (6.81 g, 25.5mmol) in THF (50 ml). The resulting orange solution was stirred for afurther 0.5 h then DMF (3.0 ml, 39 mmol, 1.5 equiv) was added at below−60° C. The reaction mixture was allowed to warm to RT, stirred for 1 h,then treated with hydrochloric acid (10%; 100 ml). After 1 h, themixture was extracted with CH₂Cl₂ (150 ml, 2×50 ml). The extract waswashed (brine; 50 ml), dried (Na₂SO₄), and concentrated in vacuo to givea yellow oil (7.0 g). The crude product was subjected to chromatography(SiO₂; Et₂O-hexane, 1:3) to afford the title compound (4.58 g) as acolourless oil δH (80 MHz; CDCl₃) 1.6-1.9 (4H, br m, CH₂(CH ₂)₂),2.4-2.65 (4H, br m, CH ₂(CH₂)₂CH ₂), 3.88 (3H, s, OMe), 6.45-6.6 (1H, brm, CH═C), 6.89 (1H, d, J 8.6 Hz, ArH ortho to OMe), 7.59 (1H, d, J 2.2Hz, ArH ortho to olefin), 7.75 (1H, dd, J 8.6, 2.2 Hz, ArH para toolefin), and 9.81 (1H, s, CHO).

INTERMEDIATE 14 2-[2-Methoxy-5-(phenylhydroxymethyl)]-1,3-dioxane

n-BuLi (1.6M solution in hexane) (115 ml, 184 mmol) was added dropwiseat ca −70° C. to a solution of Intermediate 9 (50.3 g, 184 mmol) in THF(1000 ml). A solution of benzaldehyde (20.5 g, 193 mmol) in THF (100 ml)was added dropwise at ca −70° C. and the reaction mixture allowed towarm to RT over 3 h. The mixture was quenched with 10% aqueous NH₄Clsolution (200 ml) and the organic layer separated and combined withEtOAc extracts (3×100 ml). The extract was dried (MgSO₄) andconcentrated in vacuo to afford the title compound (61.0 g) as a paleyellow crystalline solid. δH (CDCl₃) 1.47 (1H, br d, J ca 13 Hz,CH₂CHCH₂), 2.15-2.35 (2H, complex m, CH₂CHCH₂+OH), 3.82 (3H, s, OMe),3.99 (2H, ca. t, J ca. 11 Hz, CHCH₂CH), 4.23 (2H, dd, J ca. 11.4 Hz,CHCH₂CH), 5.81 (1H, s, ArCH), 5.85 (1H, s, ArCH), 6.83 (1H, d, J 8.6 Hz,ArH ortho to OMe), 7.2-7.4 (6H, m, C₆ H ₅+ArH para to dioxolane), and7.68 (1H, d, J 2.3 Hz, ArH ortho to dioxolane).

INTERMEDIATE 15 [3-(2-Dioxan-1,3-yl)-4-methoxy]benzophenone

A mixture of Intermediate 14 (60.0 g, 200 mmol) and manganese dioxide(174 g, 2.0 mol) in CH₂Cl₂ (1000 ml) was stirred at RT for 18 h. Thereaction mixture was filtered through Celite and the filtrateconcentrated in vacuo. The residue was recrystallised from diisopropylether-toluene to afford the title compound (41.0 g) as a white solid. δH(CDCl₃) 1.41 (1H, br d, J 13.5 Hz, CH₂CHCH₂), 2.1-2.3 (1H, complex m,CH₂CHCH₂), 3.93 (3H, s, OMe), 3.99 (2H, dt, J 2.1, 12.3 Hz, CHCH₂CH),4.23 (2H, dd, J 4.5, 11.5 Hz, CHCH₂CH), 5.87 (1H, s, ArCH), 6.94 (1H, d,J 8.6 Hz, ArH ortho to OMe), 7.4-7.6 (3H, m, meta and para C₆H₅), 7.75(2H, d, J 8.4 Hz ortho C₆H₅), 7.84 (1H, dd, J 2.3, 8.6 Hz, ArH para todioxane), and 8.15 (1H, dd, J 2.3 Hz, ArH ortho to dioxane).

INTERMEDIATE 16(±)-1-{3-[2-(1,3-Dioxanyl)]-4-methoxyphenyl}-1-phenyl-2-(4-pyridyl)ethanol

n-BuLi (2.5M solution in hexane) (55.6 ml, 139 mmol, 1.05 equiv.) wasadded to a solution of 4-methylpyridine (11.9 ml, 133 mmol) in THF (500ml) at −70° C. The mixture was allowed to stir at −70° C. for 0.5 h thena solution of Intermediate 15 (40.0 g, 133 mmol) in THF (250 ml) wasadded dropwise and allowed to warm to RT overnight. The reaction mixturewas quenched with 10% aqueous NH₄Cl solution (100 ml) and extracted withCH₂Cl₂ (300 ml, 100 ml). The extract was separated, dried (Na₂SO₄), andconcentrated in vacuo. The residue was recrystallised from EtOAc toafford the title compound (28.9 g) as a white crystalline solid δH(CDCl₃) 1.41 (1H, br d, J 13.5 Hz, CH₂CHCH₂), 2.15-2.25 (1H, complex m,CH₂CHCH₂), 2.4 (1H, br s, OH), 3.54 (1H, d, J 13.1 Hz, pyridine CH),3.62(1H, d, J 13.1 Hz, pyridine CH), 3.82 (3H, s, OMe), 3.99 (2H, dt, J 2.1,12.3 Hz, CHCH₂CH), 4.23 (2H, dd, J 5.1,10.7 Hz, CHCH₂CH), 5.84 (1H, s,ArCH), 6.75-6.85 (3H, m, ArH meta/para to dioxane+C₆H₅ para H),7.15-7.35 (6H, m pyridine H ₃,H ₅+C₆H₅ ortho/meta H), 7.76 (1H, d, J 2,3Hz, ArH ortho to dioxane), and 8.30 (1H, dd, J 1.5, 4.5 Hz, pyridine H₂,H ₆).

INTERMEDIATE 17(E,Z)-4-{2-[3-(2-Dioxan-1,3-yl)-4-methoxyphenyl]ethenyl}pyridine

Trifluoroacetic anhydride (11.3 ml, 80.2 mmol) was added dropwise at ca.−10° C. to a solution of Intermediate 16 (28.59 g, 72.9 mmol) andtriethylamine (15.2 ml, 109.3 mmol) in CH₂Cl₂ (500 ml). The reactionmixture was stirred at −10° C. for 0.5 h then quenched with 10% aqueoussodium carbonate solution (250 ml). The organic layer was separated andcombined with further CH₂Cl₂ extracts (3×50 ml), then dried (Na₂SO₄) andconcentrated in vacuo. The residue was subjected to chromatography(SiO₂; 5% MeOH CH₂Cl₂) to afford the title compound (20.0 g) as a yellowsolid. δH (CDCl₃) (′Hnmr indicates ca 3:1 mixture of isomers; data formajor isomer, possibly (E)-, presented) 1.43 (1H, br d, J 12.6 Hz,CH₂CHCH₂), 2.15-2.35 (1H, complex m, CH₂CHCH₂), 3.84 (3H, s, OMe), 4.01(2H, ca. t, J 11.5 Hz, CHCH₂CH), 4.26 (2H, dd, J 4.9,11.5 Hz, CHCH₂CH),5.88 (1H, s, ArCH), 6.77 (1H, d, J 8.6 Hz, ArH ortho to OMe), 6.81 (2H,d, J 5.8 Hz, pyridine H ₃, H ₅), 6.85 (1H, s, C═CH), 7.03 (1H, dd, J2.3, 8.6 Hz, ArH para to dioxane), 7.1-7.2 (2H, m, C₆H₃ H ₂), 7.3-7.35(3H, m, C₆ H ₃H₂), 7.83 (1H, d, J 2.4 Hz, ArH ortho to dioxane) and 8.30(2H, d, J 5.8 Hz, pyridine H ₂,H ₆).

INTERMEDIATE 18 2-Methoxy-5-[1-phenyl-2-(4-pyridyl)ethyl]benzaldehyde

A solution of Intermediate 17 (17.5 g, 46.8 mmol) in THF-MeOH (5:1; 1200ml) containing 10% Pd/C (0.5 g) was hydrogenated at RT over 1 h. Thereaction mixture was filtered through Celite and then concentrated invacuo. The crude alkane (15.0 g) in THF (750 ml) and 10% hydrochloricacid (75 ml) was vigorously stirred at RT for 0.5 h, then quenched withaqueous NaHCO₃ (2M; 100 ml). The organic solvent was removed in vacuoand the aqueous phase extracted with EtOAC (3×100 ml). The extract wasdried (MgSO₄) and concentrated in vacuo to afford the title compound(12.6 g). δH (CDCl₃) 3.34 (2H, d, J 8.0 Hz, CHCH ₂pyridine), 3.87 (3H,s, OMe), 4.22 (1H, t, J 8.0 Hz, CHCH₂pyridine), 6.87 (1H, d, J 8.6 Hz,ArH ortho to OMe), 6.92 (2H, d, J 6.0 Hz, H ₂, H ₆ of C₆H₅), 7.1-7.3(5H, m, pyridine H ₃, H ₅+H ₃, H ₄, H ₅ of C₆H₅), 7.32 (1H, dd,J 2.4,8.6 Hz, ArH para to CHO), 7.74 (1H, d, J 2.4 Hz, ArH ortho to CHO), 8.38(2H, ca. d, J 4.5 Hz, pyridine H ₂,H ₆) and 10.42 (1H, s, ArCHO).

INTERMEDIATE 19(±)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)-2-hydroxyethyl]pyridine

The title compound was prepared as described in the International PatentApplication No. WO94/20446.

INTERMEDIATE 20(E)-4-[2-(3-Cyclopentyloxy-4-methoxyphenyl)ethenyl]pyridine

The title compound was prepared as described in the International PatentApplication No. WO94/20446.

INTERMEDIATE 21 5-Phentylpentylbromide

To a stirred solution of 5-phenyl-1-pentanol (2.80 g, 17.07 mmol) in dryCH₂Cl₂ (80 ml) at 0° C. under a nitrogen atmosphere was added PBr₃ (4.62g, 1.62 ml. 17.07 mmol). The mixture was stirred at RT for 34 min andquenched cautiously with saturated NaHCO₃ solution (100 ml). The layerswere separated and the aqueous layer extracted with CH₂Cl₂ (2×60 ml).The combined organic extract was washed with water (80 ml), dried(MgSO₄)and the residue subjected to chromatography (SiO₂) to give thetitle compound (0.69 g) as a clear oil.

EXAMPLE 1 a)(R)-4-[2-(3-Benzyloxy-4-methoxyphenyl)-2-phenylethyl]pyridine

Potassium tert-butoxide (180 mg, 1.57 mmol) was added to a stirredsolution of Intermediate 7 (400 mg, 1.31 mmol) in THF (15 ml) and DMF (5ml). The mixture was stirred at RT for 0.25 h then treated with benzylbromide (246 mg, 1.44 mmol). After 0.5 h at RT, the reaction mixture wasquenched with water (5 ml) and concentrated in vacuo. The residue waspartitioned between water (20 ml) and EtOAc (30 ml). The organic layerwas separated and combined with further EtOAC extracts (2×30 ml). Theextract was dried (MgSO₄) and concentrated in vacuo to give a pale brownoil which was subjected to chromatography (SiO₂; EtOAc-hexane, 17:3) toafford the title compound (434 mg) as a colourless oil δH (CDCl₃) 3.18(1H, dd, J 13.6, 8.4 Hz, CHCH _(A)H_(B)), 3.25 (1H, dd, J 13.6, 7.4 Hz,CHCH_(A) H _(B)), 3.84 (3H, s, OMe), 4.09 (1H, t, J 7.9 Hz,CHCH_(A)H_(B)), 5.08 (2H, s, OCH₂), 6.58-6.8 (3H, m, C₆ H ₃), 6.82 (2H,dd, J 4.5, 1.6 Hz, pyridine H ₃, H ₅), 7.05-7.4 (10H, m, 2×C₆ H ₅), and8.35 (2H, dd, J 4.5,1.6 Hz, pyridine H ₂,H ₆).

The following Example was prepared in a manner similar to compound ofExample 1a).

b) 4-{2-(R)-[4-Methoxy-3-(phenylpentyloxy)phenyl]-2-phenylethyl}pyridine

From Intermediate 7a) (0.29 g, 0.95 mmol) in THF (5 ml) and DMF (3 ml),potassium tert-butoxide (0.12 g, 1.04 mmol) and 5-phenylbromopentane(0.26 g, 1.14 mmol) in THF (5 ml). Chromatography (SiO₂; EtOAc-hexane,1:1) gave the title compound (0.33 g) as a clear colourless oil. (FoundC, 82.16; H, 7.38; N, 3.06. C₃₁H₃₃NO₂ requires C, 82.45; H, 7.37; N,3.10%) δH (300 MHz; CDCl₃) 1.40-1.85 (6H, m, (CH ₂)₃), 2.63 (2H, t, J7.6 Hz, C₆H₅CH ₂), 3.31 (2H, d, J 7.9 Hz, CH ₂ pyridine), 3.81 (3H, s,OCH ₃), 3.90 (2H, dt, J 6.8, 1.6 Hz, OCH ₂), 4.15 (1H, t, J 9 Hz,CH₂CH), 6.65 (1H, d, J 1.8 Hz, ArH ₂), 6.7-6.8 (2H, m, ArH), 6.92 (2H,dd, J 4.6, 1.4 Hz, pyridine H ₃, H ₅), 7.15-7.30 (10H, m, 2×C₆ H ₅), and8.38 (2H, dd, J 4.5, 1.5 Hz, H ₂,H ₆ pyridine).

c) (E)-4-[4-Methoxy-3-(5-phenylpentyloxy)phenylethenyl]pyridine

From Intermediate 7b) (0.68 g, 3.0 mmol) potassium t-butoxide (0.40 g,3.6 mmol) and Intermediate 21 (0.68 g, 3.0 mmol). Chromatography (SiO₂;EtOAc-hexane, 3:1) gave a slightly off-white solid (0.874 g). A smallportion (0.34 g) was recrystallised (diisopropylether; 9 ml) to give thetitle compound (0.312 g) as an amorphous white solid (0.312 g). m.p.98-100° C. (Found C, 80.31; H, 7.27; N, 3.56. C₂₅H₂₇NO₂ requires C,80.40; H, 7.29; N, 3.7%). δH (300 MHz; CDCl₃) 1.5-2.0 (6H, m, (CH ₂)₃),2.67 (2H. t. J 7.7 Hz, ArCH ₂), 3.89 (3H, s, OCH ₃), 4.07 (2H, t, J 6.8Hz, OCH ₂), 6.86 (1H, d, J 16.3, HC═C), 6.88 (1H, d, J 8.9 Hz, ArH),7.07-7.31 (6H, m, ArH and HC═C), 7.33 (2H, dd, J 4.6, 1.5 Hz, pyridine H₃, H ₅) and 8.55 (2H, dd, J 4.6, 1.5 Hz pyridine H ₂,H ₆).

EXAMPLE 2 a)(R)-4-[2-(4-Methoxy-3-(3-thienyloxy)phenyl)-2-phenylethyl]pyridine

A mixture of Intermediate 7a) (500 mg, 1.64 mmol), anhydrous potassiumcarbonate (450 mg, 3.28 mmol) and 3-bromothiophene (3.48 g, 21.3 mmol)in pyridine (4 ml) was heated to ca. 90° C. Copper (II) oxide (330 mg,4.1 mmol) was added and the reaction mixture heated to reflux for 52 h.CH₂Cl₂ (20 ml) was added to the cooled reaction mixture which was thenfiltered. The filtrate was concentrated in vacua and the residuesubjected to chromatography (SiO₂; EtOAc-hexane, 17:3) to afford thetitle compound (315 mg), as a colourless oil. (Found C, 74.15; H, 5.40;N, 3.50. C₂₄H₂₁NO₂S requires C, 74.39; H, 5.46; N, 3.61%) δH (CDCl₃)3.24 (1H, dd, J 13.6, 8.5 Hz, CH×CH _(A)H_(B)), 3.30 (1H, dd, J 13.6,7.4 Hz, CH×CH_(A) H _(B)), 3.81 (3H, s, OMe), 4.14 (1H, t, J ca. 8.0 Hz,CH×CH_(A)H_(B)), 6.28 (1H, dd, J 3.3, 1.5 Hz, thiophene H), 6.74 (1H,dd, J 5.2, 1.5 Hz, thiophene H), 6.8-6.95 (5H, m), 7.1-7.3 (6H, m), and8.39 (2H, br s, pyridine H ₂,H ₆).

The following Examples were prepared in a manner similar to compound ofExample 2a).

b) 4-{2-(R)-[3(4Biphenyloxy)-4-methoxyphenyl)-2-phenyl]ethyl}pyridine

From Intermediate 7a) (0.4 g, 1.131 mmol), anhydrous potassium carbonate(0.36 g, 2.62 mmol), 4-bromobiphenyl (0.4 g, 1.70 mmol) and copper (II)oxide (0.26 g, 3.3 mmol). Chromatography (SiO₂; EtOAc-hexane, 1:1 then7:3) gave the title compound (0.383 g) as a clear colourless foamy oil.(Found C, 83.40; H, 5.89; N, 3.03. C₃₂H₂₇NO₂ requires C, 83.92; H, 5.95;N, 3.06%). δH (300 MHz; CDCl₃) 3.25 (1H, dd, J 13.6, 8.5 Hz, pyridineCH_(A) H _(B)), 3.25 (1H, dd, J 13.6, 7.5 Hz, pyridine CH _(A)H_(B)),3.80 (3H, s, OCH ₃), 4.16 (1H, t, C₆H₃CH), 6.85-7.0 (7H, m, ArH,pyridine H ₃, H ₅), 7,15-7.6 (12H, m, ArH) and 8.40 (2H, br s, pyridineH ₂,H ₆).

c) 4-[2-(R)-(4-Methoxy-3-phenyloxyphenyl)-2-phenylethyl]pyridine

From Intermediate 7a) (0.4 g, 1.31 mmol), anhydrous potassium carbonate(0.36 g, 2.62 mmol), bromobenzene (2.98 g, 2.0 ml, 19 mmol) and copper(II) oxide (0.26 g, 3.3 mmol). Chromatography (SiO₂; EtOAc-hexane, 17:3)gave the title compound (0.433 g) as a clear oil. (Found C, 81.45; H,5.97; N, 3.48. C₂₆H₃₂NO₂ requires C, 81.86; H, 6.08; N, 3.67%). δH (300MHz; CDCl₃) 3.24 (1H, dd, J 13.6, 8.7 Hz, pyridine CH_(A) H _(B)),3.29(1H, dd, J 13.6, 7.4 Hz, pyridine CH _(A)H_(B)), 3.78 (3H, s, OCH₃), 4.14 (1H, t, J 7.9 Hz, CH₂CH), 6.80-6.94 (7H, m, ArH, pyridine H ₃,H ₅), 7.00-7.06 (1H, m, ArH), 7,15-7.3 (7H, m, ArH) and 8.39 (2H, dd, J4.5, 1.6 Hz, pyridine H ₂,H ₆).

EXAMPLE 3(2R)-4-[2-(3-((2RS)-exo-Bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl)-2-phenylethyl]pyridine

Diethylazodicarboxylate (522 mg, 3.0 mmol) was added to a mixture ofIntermediate 7a) (610 mg, 2.0 mmol), (±)-endo-2-norborneol (224 mg, 2.0mmol), and triphenylphosphine (787 mg, 3.0 mmol) in THF (5 ml) and themixture heated to reflux for 40 h. The reaction mixture was poured intosaturated NaHCO₃ solution (10 ml) and extracted with CH₂Cl₂ (2×25 ml).The extract was dried (Na₂SO₄), concentrated in vacuo, and thensubjected to chromatography (SiO₂; Et₂O) to afford the title compound(256 mg) as a colourless oil. δH (CDCl₃) 1.0-1.75 (8H, m, norbornylH's), 2.2-2.4 (2H, br m, norbornyl H′s), 3.25-3.4 (2H, m, CHCH ₂), 3.77(3H, s, OMe), 4.05 (1H, br d, J 5.6 Hz, OCH), 4.14 (1H, t, J 7.9 Hz,CHCH₂), 6.6-6.8 (3H, m, C₆H₃), 6.92 (2H, ca. d, J 4.5 Hz, pyridine H ₃,H ₅), 7.1-7.3 (5H, m, C₆ H ₅), 8.38 (2H, ca.d, J 4.5 Hz, pyridine H ₂,H₆); m/z (El) 399 (M⁺, 8%), 307 (13), 305 (18), 213 (100), 152 (18), 95(51), 93 (19), and 67 (37).

EXAMPLE 4 a) 3-(3-Cyclopentylidenyl-4-methoxyphenyl)pyridinehydrochloride

To a solution of cyclopentyl triphenylphosphonium bromide (3.66 g, 8.9mmol) in THF (50 ml) was added dropwise n-BuLi (1.6M in hexane) (5.6 ml,9.0 mmol) at 0° C. The red solution was stirred and left to warm up toRT for 1 h then treated with a solution of Intermediate 8 (1.9 g, 8.9mmol) in THF (25 ml) at 0° C. After stirring for 1 h at RT the reactionmixture was quenched with water (50 ml) and extracted with CH₂Cl₂ (1×75,1×50, 1×25 ml). The extract was washed (brine), dried (Na₂SO₄) andconcentrated in vacuo to give a colourless syrup which crystallised togive a white solid. Purification by column chromatography [SiO₂; EtOAc]furnished the title compound free base (1.80 g) as a white solid.

A portion of the free base (388 mg) was treated with ethanolic HCl anddiluted with a little Et₂O. The precipitate was decanted, washed (Et₂O)and dried in vacuo to furnish the title compound (420 mg) as a paleyellow solid (Found: C, 71.56; H, 6.68; N, 4.74. C₁₈H₁₉NO. HCl requiresC, 71.63; H, 6.68; N, 4.64%). δH (80 MHz; CDCl₃) 1.6-1.9 (4H, br m,CH₂(CH ₂)₂CH₂), 2.4-2.65 (4H, br m, CH ₂(CH₂)₂CH ₂), 3.89 (3H, s, OMe),6.5-6.6 (1H, br m, HC═C), 6.97 (1H, d, J 8.6 Hz, ArH ortho to OMe), 7.40(1H, dd, J 8.6, 2.2 Hz, ArH para to C═C), 7.53 (1H, d J 2.2 Hz, ArHortho to C═C), 7.9 (1H, dd, J 5.6, 8.3 Hz, pyridine H ₅), 8.4-8.7 (2H,m, pyridine H ₄, H ₆) and 8.85 (1H, d, J 2.2 Hz, pyridine H ₂).

b)4-[2-(3-Cyclopentylidenylmethyl-4-methoxyphenyl)2-phenylethyl]pyridinehyrochloride hemihydrate

From n-BuLi (1,6M solution in hexane) (2.1 ml, 3.55 mmol, 1.06 equiv),cyclopentyltriphenylphosphonium bromide (1.43 g, 3.46 mmol, 1.1 equiv)in THF (30 ml) and Intermediate 18 (1.00 g, 3.15 mmol) in THF (20 ml).Chromatography (SiO₂; 2% MeOH—CH₂Cl₂) afforded the title compound freebase (420 mg). δH (CDCl₃) 1.6-1.8 (4H, br m, CH₂(CH ₂)₂CH₂), 2.2-2.35(2H, br m, CH(CH₂)₂CH), 2.4-2.55 (2H, br m, CH(CH₂)₂CH), 3.22 (2H, d, J7.8 Hz, CHCH ₂ pyridine), 3.78 (3H, s, OMe), 4.17 (1H, t, J 7.8 Hz,CHCH₂ pyridine), 6.51 (1H, ca. t, J 2.2 Hz, HC═CCH₂), 6.72 (1H, d, J 8.4Hz, ArH ortho to OMe), 6.85-7.0 (3H, m, Hof C₆H₃+pyridine H ₃, H ₅),7.1-7.3 (6H, m, C₆ H ₅+Hof C₆H₃) and 8.38 (2H, ca. d, J 5.7 Hz, pyridineH ₂, H ₆).

The base (420 mg) was dissolved in Et₂O (5 ml) and treated dropwise withethanolic HCl. The precipitated product was collected by filtration anddried in vacuo to afford the title compound as a white solid (Found: C,75.23; H, 6.72; N, 3.11; C₂₆H₂₈NO. 0.5H₂O requires C, 75.25; H, 7.04; N,3.38%). δH (CDCl₃) 1.6-1.8 (4H, br m, CH₂(CH ₂)₂CH₂), 2.2-2.35 (2H, brm, CH(CH₂)₂CH), 2.4-2.55 (2H, br m, CH(CH₂)₂CH), 3.59 (2H, d, J 8.0 Hz,CHCH ₂ pyridine), 3.80 (3H, s, OMe), 4.18 (1H, t, J 8.0 Hz, CHCH₂pyridine), 6.51 (1H, ca. t, J 2.0 Hz, CH═CCH₂), 6.73 (1H, d, J 8.4 Hz,ArH ortho to OMe), 6.87 (1H, dd, J 2.2, 8.4 Hz, ArH para to olefin),7.1-7.45 (6H, m, C₆ H ₅+ArH ortho to olefin), 7.46 (2H, ca. d, J ca. 6.4Hz, pyridine H ₃, H ₅), and 8.50 (2H, ca. d, J ca. 6.4 Hz, pyridine H ₂,H ₆); m/z (ESI) 370 (M ⁺+1-HCl, 18%), 369 (M ⁺-HCl, 95), 277 (100), 178(55), 165 (75), and 152 (45).

c)4-[2-(3-Cyclohexylidenylmethyl-4-methoxyphenyl)-2-phenyl-ethyl]pyridinehydrochloride

From Intermediate 18 (1.00 g, 3.15 mmol), cyclohexyltriphenylphosphoniumbromide (1.47 g, 3.46 mmol, 1.1 equiv) and n-BuLi (1.6 M solution inhexane) (2.1 ml, 3.36 mmol, 1.07 equiv). The crude product was subjectedto chromatography (SiO₂; 2% MeOH—CH₂Cl₂) to afford the title compoundfree base (1.07 g).

A portion of the free base (400 mg) was dissolved in Et₂O (5 ml) andtreated with ethanolic HCl to afford the title compound as a white solid(Found: C, 77.32; H, 7.15; N, 3.24. C₂₇H₃₀ClNO requires C, 77.21; H,7.20; N, 3.34%). δH (CDCl₃) 1.4-1.75 (6H, br m, CH₂(CH)₃CH₂), 2.0-2.1(2H, br m, CH(CH₂)₃CH), 2.2-2.3 (2H, br m, CH(CH₂)₃CH), 3.58(2H, d, J8.0 Hz, CHCH ₂ pyridine), 3.78 (3H, s, OMe), 4.18 (1H, t, J 8.0 Hz,CHCH₂ pyridine), 6.15 (1H, ca. s, HC═CCH₂), 6.73 (1H, d, J 9.0 Hz, ArHortho to OMe), 6.85-6.95 (2H, m, ArH), 7.1-7.35 (5H, m, ArH), 7.46 (2H,d, J 5.8 Hz, pyridine H3, H ₅), and 8.50 (2H, d, J 5.8 Hz, pyridine H ₂,H ₆); m/z (ESI) 384 (M ⁺+1-HCl, 37%), 383 (M ⁺-HCl, 85), 291 (100), 178(32), 165 (50), 152 (28) and 91 (33).

d)4-{2(R)-[3-(Phenyl-1,3-butedienyl)-4-methoxyphenyl]-2-phenylethyl}pyridine

From n-BuLi (1.6M solution in hexane) (1.2 ml, 2.93 mmol, 1.05 equiv).cinnamyltriphenylphosphonium bromide (930.6 mg, 2.02 mmol) andIntermediate 9 (583.9 mg, 1.84 mmol). Chromatography (SiO₂;EtOAc-hexane, 1:1) gave the title compound.

EXAMPLE 5 a) 3-(3-Cyclopentylmethyl-4-methoxyphenyl) pyridinehydrochloride

The compound of Example 4a) (485 mg) was hydrogenated over the weekendin EtOH (25 ml) in the presence of 5% Pd/C (50 mg). The reaction mixturewas filtered through Celite and concentrated in vacuo to give the titlecompound free base (464 mg) as a colourless oil.

The free base was dissolved in warm ethanolic HCl, precipitated withEt₂O, decanted and dried in vacuo to yield the title compound (485 mg)as a white solid. (Found: C, 70.98; H, 7.31; N, 4,62. C₁₈H₂₁NO. HClrequires C, 71.16; H, 7.30; N, 4.61%). δH (80 MHz; CDCl₃) 1.5-1.8 ((H,v.br m, cyclopentyl H's), 2.67 (2H, d, J 6.8 Hz,CH ₂ cyclopentyl), 3.87(3H, s, OMe), 6.95 (1H, d, J 8.0 Hz, ArH ortho to OMe), 7.35-7.50 (2H,m, 2×ArH meta to OMe), 7.8-8.0 (1H, m, pyridine H ₅), 8.4-8.65 (2H, m,pyridine H) and 8.87 (1H, ˜d, J 2.0 Hz, pyridine H ₂).

The following compound was prepared in a manner similar to the compoundof Example 5a).

b) 4-{2-[4-Methoxy-3-(5-phenylpentyloxy)phenylethyl}pyridine

From the compound of Example 1c) (0.534 g, 1.43 mmol) and 5% Pd/Ccatalyst (40 mg). Chromatography (SiO₂; EtOAc-hexane, 3:1) gave a clearcolourless oil which solidified to give the title compound (0.45 g) as awhite amorphous solid. m.p. 59-62° C. (Found C, 79.63; H, 7.79; N, 3.57.C₂₅H₂₉NO₂ requires C, 79.96; H, 7.78; N, 3.73%) δH (300 MHz; CDCl₃)1.4-1.9 (6H, br m, (CH ₂)₃), 2.65 (2H, t, J 7.7 Hz, ArCH ₂), 2.83-2.91(4H, m, (CH ₂)₂), 3.83 (3H, s, OCH ₃), 3.94 (2H, t, J 6.8 Hz, OCH ₂),6.63 (1H, d, J 2.0 Hz, ArH ₂), 6.66 (1H, dd, J 8.0, 2.0 Hz, ArH6), 6.78(1H, d, J 8.1 Hz, ArH ₄), 7.06 (2H, dd, J 4.4, 1.6 Hz, pyridine H3, H₅), 7.15-7.3 (5H, m, ArH), and 8.47 (2H, dd, J 4.4, 1.6 Hz, pyridine H₂, H ₆).

c) 4-[2-(4-Methoxy-3-butylphenyl)-2-phenylethyl]pyridine hydrochloride

From the compound of Example 4d). Chromatography (SiO₂; EtOAc-hexane,1:9) gave the title compound free base as a colourless oil. The freebase was treated with ethanolic HCl to give the title compound as anoff-white solid. (Found C, 78.13; H, 6.98; N, 3.02 C₃₀H₃₂NOCl requiresC, 78.67; H, 7.04; N, 3.06%). δ_(H) (CDCl₃) 1.55 (4H, m, CH₂(CH ₂)CH₂),2.60 (4H, m, CH ₂(CH₂)₂CH₂), 3.55 (2H, d, pyridine (CH ₂), 3.75 (3H, S,OCH ₃), 4.15 (1H, t, ArCH), 6.70 (m, ArH), 6.90 (2H, m, ArH), 7.10-7.30(10H, m, 2×C₆ H ₅), 7.4 (2H, d, ArH) and 8.55 (2H, d, ArH).

EXAMPLE 6 Methyl 3-[Cyclopentylidenyl-4-methoxyphenyl]propenoate

A mixture of trimethylphosphonoacetate (2.7 g, 14.8 mmol) andIntermediate 13 (3.009, 13.9 mmol) in MeOH (30 ml) was added to asolution of sodium methoxide [prepared from sodium (0.4 g, 17.4 mmol) inMeOH (50 ml) at RT]. The reaction mixture was stirred at RT overnightthen the crystalline product collected by filtration, washed with MeOH(2×10 ml), and dried in vacuo to afford the title compound (2.70 g) as awhite solid (Found: C, 74.73; H, 7.43 C₁₇H₂₀O₃ requires: C, 74.97; H,7.40%); δH (80 MHz; CDCl₃) 1.5-1.8 (4H, br m, CH₂(CH ₂)₂), 2.4-2.6 (4H,br m, CH ₂(CH₂)₂CH ₂), 3.77 (3H, s, OMe), 6.25 (1H, d, J 15.8 Hz,CH═CH), 6.45-6.55 (1H, br m, CH═CCH₂), 6.80 (1H, d, J 8.7 Hz, ArH orthoto OMe), 7.28 (1H, dd, J 8.7, 2.6 Hz, ArH para to cyclopentylidene),7.48 (1H, d, J 2.6 Hz, ArH ortho to cyclopentylidene), and 7.61 (1H, d,J 15.8 Hz, CH═CH); m/z (El) 273 (M⁺+1, 18%), 272 (100), 241 (11), 239(11), 225 (11), 205 (19), 192 (17), 175 (11), 161 (17), and 115 (18).

The activity and selectivity of compounds according to the invention wasdemonstrated in the following tests. In these tests the abbreviationFMLP represents the peptide N-formyl-met-leu-phe.

1. Isolated Enzyme

The potency and selectivity of the compounds of the invention wasdetermined using distinct PDE isoenzymes as follows:

i. PDE I, rabbit heart

ii. PDE II, rabbit heart

iii. PDE III, rabbit heart, Jurkat cells

iv. PDE IV, HL60 cells, rabbit brain, rabbit kidney and humanrecombinant PDE IV

v. PDE V, rabbit lung, guinea pig lung

A gene encoding human PDE IV has been cloned from human monocytes (Livi,et al., 1990, Molecular and Cellular Biology, 10, 2678). Using similarprocedures we have cloned human PDE IV genes from a number of sourcesincluding eosinophils, neutrophils, lymphocytes, monocytes, brain andneuronal tissues. These genes have been transfected into yeast using aninducible vector and various recombinant proteins have been expressedwhich have the biochemical characteristics of PDE IV (Beavo andReifsnyder, 1990, TIPS, 11, 150). These recombinant enzymes,particularly the human eosinophil recombinant PDE IV, have been used asthe basis of a screen for potent, selective PDE IV inhibitors.

The enzymes were purified to isoenzyme homogeneity using standardchromatographic techniques.

Phosphodiesterase activity was assayed as follows. The reaction wasconducted in 150 μl of standard mixture containing (finalconcentrations): 50 mM2-[[tris(hydroxymethyl)methyl]amino]-1-ethanesulphonic acid (TES) —NaOHbuffer (pH 7.5), 10 mM MgCl₂ , 0.1 μM [ ³H]-cAMP and vehicle or variousconcentrations of the test compounds. The reaction was initiated byaddition of enzyme and conducted at 30° C. for between 5 to 30 min. Thereaction was terminated by addition of 50 μl 2% trifluoroacetic acidcontaining [¹⁴C]-5′AMP for determining recovery of the product. Analiquot of the sample was then applied to a column of neutral aluminaand the [³H]-cAMP eluted with 10 ml 0.1 TES-NaOH buffer (pH8). The[³H]-5′-AMP product was eluted with 2 ml 2M NaOH into a scintillationvial containing 10 ml of scintillation cocktail. Recovery of [3H]-5′AMPwas determined using the [¹⁴C]-5′AMP and all assays were conducted inthe linear range of the reaction.

Compounds according to the invention such as compounds of the Examplesherein cause a concentration-dependent inhibition of recombinant PDE IVat 0.1-1000 nM with little or no activity against PDE I, II, III or V atconcentrations up to 100 μM.

2. The Elevation of cAMP in Leukocytes

The effect of compounds of the invention on intracellular cAMP wasinvestigated using human neutrophils or guinea pig eosinophils. Humanneutrophils were separated from peripheral blood, incubated withdihydrocytochalasin B and the test compound for 10 min and thenstimulated with FMLP. Guinea pig eosinophils were harvested byperitoneal lavage of animals previously treated with intra-peritonealinjections of human serum. Eosinophils were separated from theperitoneal exudate and incubated with isoprenaline and test compound.With both cell types, suspensions were centrifuged at the end of theincubation, the cell pellets were resuspended in buffer and boiled for10 min prior to measurement of cAMP by specific radioimmunoassay(DuPont).

The most potent compounds according to the Examples induced aconcentration-dependent elevation of cAMP in neutrophils and/oreosinophils at concentrations of 0.1 nM to 1 μM.

3. Suppression of Leukocyte Function

Compounds of the invention were investigated for their effects onsuperoxide generation, chemotaxis and adhesion of neutrophils andeosinophils. Isolated leukocytes were incubated withdihydrocyto-chalasin B for superoxide generation only and test compoundprior to stimulation with FMLP. The most potent compounds of theExamples caused a concentration-dependent inhibition of superoxidegeneration, chemotaxis and adhesion at concentrations of 0.1 nM to 1 μM.

Lipopolysaccharide (LPS)-induced synthesis of tumour necrosis factor(TNF) by human peripheral blood monocytes (PBM) is inhibited bycompounds of the Examples at concentrations of 0.01 nM to 10 μM.

4. Adverse Effects

In general, in our tests, compounds of the invention have had noobserved toxic effects when administered to animals at pharmacologicallyeffect doses.

What is claimed is:
 1. A compound of formula (1)

wherein ═W— is (1) ═C(Y)— or (2) ═N—; L is (1) —C(R)═C(R¹)(R²) or—(CHR)_(n)CH(R¹)(R²), (2) —(X^(a))_(n)Alk′Ar′ or —Alk′X^(a)Ar′ or (3)X^(a)R′; Z is a group (A), (B), (C) or (D):

n is zero or the integer 1; t is zero or an integer 1, 2 or 3; Y ishalogen or an alkyl or —XR^(a) group; each of X and X^(a) isindependently —O—, —S(O)_(m)—, or —N(R^(b))—; Z¹ is —NR¹²C(O)—,—C(O)NR¹²—, —NR¹²C(S)—, —C(S)NR¹²—, —C≡C—, —NR¹²SO₂— or —SO₂NR¹²—; m iszero or an integer 1 or 2; each of R^(a) and R^(b) is independentlyhydrogen or an optionally substituted alkyl group; R′ is Ar′ or anoptionally substituted polycycloalkyl or polycycloalkenyl groupoptionally containing one or more —O— or —S— atoms or —N(R^(b))— groups;Ar is an optionally substituted monocyclic or bicyclic aryl groupoptionally containing one or more heteroatoms selected from oxygen,sulphur and nitrogen atoms; Ar′ is an optionally substitutedheterocycloaliphatic group or an optionally substituted monocyclic orbicyclic aryl group optionally containing one or more heteroatomsselected from oxygen, sulfur and nitrogen atoms; Alk is an optionallysubstituted straight or branched alkylene chain optionally interruptedby an atom or group X; Alk′ is an optionally substituted straight orbranched alkylene, alkenylene or alkynylene chain optionally interruptedby one or more linker atoms or groups L¹; R is hydrogen, fluorine or amethyl group; each of R¹ and R², which may be the same or different, ishydrogen, fluorine, —CN, —NO₂, or an optionally substituted alkyl,alkenyl, alkynyl, alkoxy, alkylthio, —CO₂R⁸, —CONR⁹R¹⁰ or —CSNR⁹R¹⁰group, or R¹ and R², together with the carbon atom to which they areattached, are linked to form an optionally substituted cycloalkyl,cycloalkenyl or heterocycloaliphatic group; R³ is hydrogen, fluorine, anoptionally substituted straight or branched alkyl group, or —OR¹¹; R⁴ ishydrogen, —CN, —CH₂CN or an optionally substituted —CO₂R⁸, —CSNR⁹R¹⁰ or—(CH₂)_(t)Ar group; R⁵ is —(CH₂)_(t)Ar; R⁶ is hydrogen, fluorine,—CO₂R⁸, —CONR⁹R¹⁰, —CSNR⁹R¹⁰, or an optionally substituted alkyl group;R⁷ is hydrogen, fluorine, an optionally substituted straight or branchedalkyl group, or —OR^(c), where R^(c) is hydrogen, formyl or anoptionally substituted alkyl, alkenyl, alkoxyalkyl, alkanoyl,carboxamido or thiocarboxamido group; each of R⁸, R⁹ and R¹⁰ isindependently hydrogen or an optionally substituted alkyl, aralkyl oraryl group; R¹¹ is hydrogen, formyl or an optionally substituted alkyl,alkenyl, alkoxyalkyl, alkanoyl, carboxamido or thiocarboxamido group;R¹² is hydrogen or an optionally substituted alkyl or —(Alk)_(t)Argroup; and the salts, solvates, hydrates, prodrugs and N-oxides thereof;with the provisos that when L is a group (2) or (3), then Z is a group(A) or (B) in which R⁴ is —(CH₂)_(t)Ar, when W is ═N—, L is methyl, Z isa group (A) or (B) and R⁵ is phenyl, then at least one of R³, R⁴, R⁶ andR⁷ is other than hydrogen within the atoms or groups defined for R³, R⁴,R⁶ R⁷ hereinabove, when W is ═N—, L is methyl, Z is a group (D), Z¹ is—C(O)NH— and Ar is phenyl, then n is 1 and/or t is 1, 2 or 3, when W isC(OCH₃), L is bicyclo(2.2.1)heptyloxy, Z is a group (B), and R⁴ and R⁶are hydrogen, then R⁵ is other than 4-(methoxycarbonyl)phenyl within thegroups defined for R⁵ hereinabove, when W is C(OCH₃), L is[exo-8,9,10-trinorbornyl-2-oxy] tricycloalkyloxy or benzyloxy, Z is agroup D, Z¹ is —C(O)NH— and Ar is 3,5-dichloropyrid-4-yl,2,6-dichlorophenyl or unsubstituted phenyl, then n is 1 and/or t is 1, 2or 3, and when W is C(OCH₃) and L is benzyloxy, then Z is other than agroup (C) in which Ar is an optionally substituted nitrogen-containingmonocyclic or bicyclic heterocycle within the groups defined for Arhereinabove.
 2. A compound according to claim 1 wherein W is a ═C(Y)—group.
 3. A compound according to claim 2 wherein Y is an XR^(a) group.4. A compound according to claim 3 wherein L is a —C(R)═C(R¹)(R²) groupin which R¹ and R², together with the C atom to which they are attachedare linked to form a cycloalkyl group.
 5. A compound according to claim1 wherein Z is a group (A) or (B), in which R³, R⁶ and R⁷ is each ahydrogen atom, R⁴ is an aryl group and R⁵ is a heteroaryl group.
 6. Acompound according to claim 5 wherein R⁴ is an optionally substitutedphenyl group and R⁵ is an optionally substituted pyridyl group.
 7. Acompound which is selected from the group consisting of:4-{2-[4-Methoxy-3-(phenylpentyloxy)phenyl]-2-phenylethyl}pyridine;4-[2-(4-Methoxy-3-(3-thienyloxy)phenyl)-2-phenylethyl]pyridine;4-{2-[3-(4-Biphenyloxy)-4-methoxyphenyl]-2-phenylethyl}pyridine;4-[2-(3-((2RS)-exo-Bicyclo[2.2.1]hept-2-yloxy)-4-methoxyphenyl)-2-phenylethyl]pyridine;3-(3-Cyclopentylidenyl-4-methoxyphenyl)pyridine; the resolvedenantiomers; and the salts, solvates, hydrates, prodrugs and N-oxidesthereof.
 8. A pharmaceutical composition which comprises a compound offormula (1)

wherein ═W— is (1) ═C(Y)— or (2) ═N—; L is (1) —C(R)═C(R¹)(R²) or—(CHR)_(n)CH(R¹)(R²), (2) —(X^(a))_(n)Alk′Ar′ or —Alk′X^(a)Ar′ or (3)X^(a)R′; Z is a group (A), (B), (C) or (D):

n is zero or the integer 1; t is zero or an integer 1, 2 or 3; Y ishalogen or an alkyl or —XR^(a) group; each of X and X^(a)isindependently —O—, —S(O)_(m)—, or —N(R^(b))—; Z¹ is —NR¹²C(O)—,—C(O)NR¹²—, —NR¹²C(S)—, —C(S)NR¹²—, —C≡C—, —NR¹²SO₂— or —SO₂NR¹²—; m iszero or an integer 1 or 2; each of R^(a) and R^(b) is independentlyhydrogen or an optionally substituted alkyl group; R′ is Ar′ or anoptionally substituted polycycloalkyl or polycycloalkenyl groupoptionally containing one or more —O— or —S— atoms or —N(R^(b))— groups;Ar is an optionally substituted monocyclic or bicyclic aryl groupoptionally containing one or more heteroatoms selected from oxygen,sulphur and nitrogen atoms; Ar′ is an optionally substitutedheterocycloaliphatic group or an optionally substituted monocyclic orbicyclic aryl group optionally containing one or more heteroatomsselected from oxygen, sulfur and nitrogen atoms; Alk is an optionallysubstituted straight or branched alkylene chain optionally interruptedby an atom or group X; Alk′ is an optionally substituted straight orbranched alkylene, alkenylene or alkynylene chain optionally interruptedby one or more linker atoms or groups L¹; R is hydrogen, fluorine or amethyl group; each of R¹ and R², which may be the same or different, ishydrogen, fluorine, —CN, —NO₂, or an optionally substituted alkyl,alkenyl, alkynyl, alkoxy, alkylthio, —CO₂R⁸, —CONR⁹R¹⁰ or —CSNR⁹R¹⁰group, or R¹ and R², together with the carbon atom to which they areattached, are linked to form an optionally substituted cycloalkyl,cycloalkenyl or heterocycloaliphatic group; R³ is hydrogen, fluorine, anoptionally substituted straight or branched alkyl group, or —OR¹¹; R⁴ ishydrogen, —CN, —CH₂CN or an optionally substituted —CO₂R⁸, —CSNR⁹R¹⁰ or—(CH₂)_(t)Ar group; R⁵ is —(CH₂)_(t)Ar; R⁶ is hydrogen, fluorine,—CO₂R⁸, —CONR⁹R¹⁰, —CSNR⁹R¹⁰, or an optionally substituted alkyl group;R⁷ is hydrogen, fluorine, an optionally substituted straight or branchedalkyl group, or —OR^(c), where R^(c) is hydrogen, formyl or anoptionally substituted alkyl, alkenyl, alkoxyalkyl, alkanoyl,carboxamido or thiocarboxamido group; each of R⁸, R⁹ and R¹⁰ isindependently hydrogen or an optionally substituted alkyl, aralkyl oraryl group; R¹¹ is hydrogen, formyl or an optionally substituted alkyl,alkenyl, alkoxyalkyl, alkanoyl, carboxamido or thiocarboxamido group;R¹² is hydrogen or an optionally substituted alkyl or —(Alk)_(t)Argroup; and the salts, solvates, hydrates, prodrugs and N-oxides thereof;with the provisos that when L is a group (2) or (3), then Z is a group(A) or (B) in which R⁴ is —(CH₂)_(t)Ar, when W is ═N—, L is methyl, Z isa group (A) or (B) and R⁵ is phenyl, then at least one of R³, R⁴, R⁶ andR⁷ is other than hydrogen within the atoms or groups defined for R³, R⁴,R⁶ R⁷ hereinabove, when W is ═N—, L is methyl, Z is a group (D), Z¹ is—C(O)NH— and Ar is phenyl, then n is 1 and/or t is 1, 2 or 3, when W isC(OCH₃), L is bicyclo(2.2.1)heptyloxy, Z is a group (B), and R⁴ and R⁶are hydrogen, then R⁵ is other than 4-(methoxycarbonyl)phenyl within thegroups defined for R⁵ hereinabove, when W is C(OCH₃), L is[exo-8,9,10-trinorbornyl-2-oxy] tricycloalkyloxy or benzyloxy, Z is agroup D, Z¹ is —C(O)NH— and Ar is 3,5-dichloropyrid-4-yl,2,6-dichlorophenyl or unsubstituted phenyl, then n is 1 and/or t is 1, 2or 3, and when W is C(OCH₃) and L is benzyloxy, then Z is other than agroup (C) in which Ar is an optionally substituted nitrogen-containingmonocyclic or bicyclic heterocycle within the groups defined for Arhereinabove; together with one or more pharmaceutically acceptablecarriers, excipients or diluents.
 9. A compound of formula (2)

wherein L is (1) —C(R)═C(R¹)(R²) or —CH₂CH(R¹)(R²), (2) —OAlkAr′, or (3)—OR′; Z is a group (A), (B), (C) or (D):

n is zero or the integer 1; t is zero or an integer 1, 2 or 3; X is —O—,—S(O)_(m)—, or —N(R^(b))—; Z¹ is —NR¹²C(O)—, —C(O)NR¹²—, —NR¹²C(S)—,—C(S)NR¹²—, —C≡C—, —NR¹²SO₂— or —SO₂NR¹²—; m is zero or an integer 1 or2; R^(b) is hydrogen or an optionally substituted alkyl group; R′ is Ar′or an optionally substituted polycycloalkyl or polycycloalkenyl group;Ar is an optionally substituted monocyclic or bicyclic aryl groupoptionally containing one or more heteroatoms selected from oxygen,sulphur and nitrogen atoms; Ar′ is a monocyclic or bicyclic aryl orheteroaryl group; Alk is a C₁₋₆alkylene chain; R is hydrogen, fluorineor a methyl group; R¹ and R² are linked together with the carbon atom towhich they are attached to form a cycloalkyl group; R³ is hydrogen,fluorine, an optionally substituted straight or branched alkyl group, or—OR¹¹; R⁴ is hydrogen, —CN, —CH₂CN or an optionally substituted —CO₂R⁸,—CSNR⁹R¹⁰ or —(CH₂)_(t)Ar group; R⁵ is —(CH₂)_(t)Ar; R⁶ is hydrogen,fluorine, —CO₂R⁸, —CONR⁹R¹⁰, —CSNR⁹R¹⁰, or an optionally substitutedalkyl group; R⁷ is hydrogen, fluorine, an optionally substitutedstraight or branched alkyl group, or —OR^(c), where R^(c) is hydrogen,formyl or an optionally substituted alkyl, alkenyl, alkoxyalkyl,alkanoyl, carboxamido or thiocarboxamido group; each of R⁸, R⁹ and R¹⁰is independently hydrogen or an optionally substituted alkyl, aralkyl oraryl group; R¹¹ is hydrogen, formyl or an optionally substituted alkyl,alkenyl, alkoxyalkyl, alkanoyl, carboxamido or thiocarboxamido group;R¹² is hydrogen or an optionally substituted alkyl or —(Alk)_(t)Argroup; and the salts, solvates, hydrates, prodrugs and N-oxides thereof;with the provisos that when L is a group (2) or (3), then Z is a group(A) or (B) in which R⁴ is —(CH₂)_(t)Ar, when L isbicyclo(2.2.1)heptyloxy, Z is a group (B), and R⁴ and R⁶ are hydrogen,then R⁵ is other than 4-(methoxycarbonyl)phenyl within the groupsdefined for R⁵ hereinabove, when L is [exo-8,9,10-trinorbornyl-2-oxy]tricycloalkyloxy or benzyloxy, Z is a group D, Z¹ is —C(O)NH— and Ar is3,5-dichloropyrid-4-yl, 2,6-dichlorophenyl or unsubstituted phenyl, thenn is 1 and/or t is 1, 2 or 3, and when W is C(OCH₃) and L is benzyloxy,then Z is other than a group (C) in which Ar is an optionallysubstituted nitrogen-containing mocyclic or bicyclic heterocycle withinthe groups defined for Ar hereinabove.
 10. A compound according to claim9 wherein L is —OAlk′Ar′.
 11. A compound according to claim 10 wherein Lis selected from benzyloxy, thienyloxy and phenylpentyloxy.
 12. Acompound according to claim 9 wherein L is OR′.
 13. A compound accordingto claim 12 wherein R′ is optionally substituted bicyclo(2.2.1)heptyl orbicyclo(2.2.1)heptenyl.
 14. A compound according to claim 12 wherein Zis group (A).
 15. A compound according to claim 14 wherein R³, R⁶ and R⁷are hydrogen.
 16. A compound according to claim 15 wherein R′ isbicyclo(2.2.1)heptyl.
 17. A compound according to claim 15 wherein R⁴ isoptionally substituted phenyl or optionally substituted pyridyl, and R⁵is optionally substituted pyridyl.